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International Journal of Nanomedicine
ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/dijn20
Nanoparticles in Combating Neuronal

Dysregulated Signaling Pathways: Recent
Approaches to the Nanoformulations of
Phytochemicals and Synthetic Drugs Against
Neurodegenerative Diseases
Sajad Fakhri, Sadaf Abdian, Seyede Nazanin Zarneshan, Seyed Zachariah

Moradi, Mohammad Hosein Farzaei & Mohammad Abdollahi
To cite this article: Sajad Fakhri, Sadaf Abdian, Seyede Nazanin Zarneshan, Seyed Zachariah
Moradi, Mohammad Hosein Farzaei & Mohammad Abdollahi (2023) Nanoparticles
in Combating Neuronal Dysregulated Signaling Pathways: Recent Approaches to the
Nanoformulations of Phytochemicals and Synthetic Drugs Against Neurodegenerative
Diseases, International Journal of Nanomedicine, , 299-331, DOI: 10.2147/IJN.S347187
To link to this article: https://doi.org/10.2147/IJN.S347187
© 2022 Fakhri et al. Published online: 22 Jan 2022.
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REVIEW
Nanoparticles in Combating Neuronal Dysregulated

Signaling Pathways: Recent Approaches to the
Nanoformulations of Phytochemicals and Synthetic
Drugs Against Neurodegenerative Diseases
Sajad Fakhri 1 Abstract: As the worldwide average life expectancy has grown, the prevalence of age-
Sadaf Abdian 2, * related neurodegenerative diseases (NDDs) has risen dramatically. A progressive loss of
Seyede Nazanin Zarneshan2,* neuronal function characterizes NDDs, usually followed by neuronal death. Inflammation,
Seyed Zachariah Moradi 1,3 apoptosis, oxidative stress, and protein misfolding are critical dysregulated signaling path-
ways that mainly orchestrate neuronal damage from a mechanistic point. Furthermore, in
Mohammad Hosein Farzaei 1
afflicted families with genetic anomalies, mutations and multiplications of α-synuclein and
Mohammad Abdollahi 4,5
amyloid-related genes produce some kinds of NDDs. Overproduction of such proteins, and
1
Pharmaceutical Sciences Research their excessive aggregation, have been proven in various models of neuronal malfunction and
Center, Health Institute, Kermanshah
University of Medical Sciences, death. In this line, providing multi-target therapies carried by novel delivery systems would
Kermanshah, Iran; 2Student Research pave the road to control NDDs through simultaneous modulation of such dysregulated
Committee, Kermanshah University of pathways. Phytochemicals are multi-target therapeutic agents, which employ several
Medical Sciences, Kermanshah, Iran;
3
Medical Biology Research Center, mechanisms towards neuroprotection. Besides, the blood–brain barrier (BBB) is a critical
Kermanshah University of Medical issue in managing NDDs since it inhibits the accessibility of drugs to the brain in sufficient
Sciences, Kermanshah, Iran; 4Toxicology
concentration. Besides, discovering novel delivery systems is vital to improving the efficacy,
and Diseases Group, Pharmaceutical
Sciences Research Center (PSRC), The bioavailability, and pharmacokinetic of therapeutic agents. Such novel formulations are also
Institute of Pharmaceutical Sciences employed to improve the drug’s biodistribution, allow for the co-delivery of several medi-
(TIPS), Tehran University of Medical
Sciences, Tehran, Iran; 5Department of cines, and offer targeted intracellular delivery against NDDs. The present review proposes
Toxicology and Pharmacology, School of nanoformulations of phytochemicals and synthetic agents to combat NDDs by modulating
Pharmacy, Tehran University of Medical neuroinflammation, neuroapoptosis, neuronal oxidative stress pathways and protein
Sciences, Tehran, Iran
misfolding.
*These authors contributed equally to Keywords: neuroprotection, apoptosis, inflammation, oxidative stress, novel delivery
this work
system, therapeutic target, pharmacology
Introduction
In recent decades, nanoparticles have shown significant implications in improving
biodegradability/biocompatibility, therapeutic effectiveness, and drug pharmacoki-
netics while decreasing the adverse effects of current medications.1–3 The blood–
brain barrier (BBB) is a critical issue in managing neurodegenerative diseases
(NDDs) since it inhibits the accessibility of drugs to the brain in sufficient ther-
Correspondence: Mohammad Hosein apeutic concentrations. The functional intricacy of the BBB is mainly ascribed to
Farzaei; Mohammad Abdollahi the brain capillary endothelial cells, which limit trans-cellular transit, as well as the
Email mh.farzaei@gmail.com;
Mohammad@TUMS.Ac.Ir tight and adherens junctions between the cells, which result in the limitation of
International Journal of Nanomedicine 2022:17 299–331 299

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work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
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Fakhri et al Dovepress
para-cellular flow. Thus, to overcome the pharmacokinetic pathways.1 The current study aims to develop nanoparti-
limitations of drugs used against NDDs, employing novel cles’ therapeutic potential in combating neuroinflamma-
delivery systems would be helpful.4 tion, neuroapoptosis, neuronal oxidative stress and
By passing BBB, nanoparticles have shown the poten- protein aggregation with a promising approach to the
tial of regulating several dysregulated pathways in NDDs, nanoformulations of phytochemicals and synthetic drugs
including oxidative stress,1,2 inflammation,5 apoptosis,6,7 against NDDs.
and protein aggregation.8 Oxidative stress is commonly
defined as a discrepancy between the activity of antiox- How Nanoformulations Modulate
idants and the generation of oxidants, which shows nega- Neuronal Oxidative Stress,
tive health benefits to play a fundamental part in the
aggravation of several diseases.1,2,6,9–11 Modulating oxida-
Inflammation, Apoptosis, and
tive stress is one of the most effective support mechanisms Proteins Aggregation in NDDs
of nanoparticles against NDDs.1,2 Furthermore, neuroin- The term nanoparticles predominantly refer to small struc-
flammation is defined as a critical activator of the brain’s tures with size ranges from 1 to 100 nm that could be
innate immune system in a complicated pattern to an categorized according to their shapes, properties, or sizes.
inflammatory state related to numerous molecular and Carbon-based (carbon nanotubes and fullerenes), ceramic,
cellular changes inside the brain. These changes inhibit metal, semiconductor, lipid-based, polymeric
glial cell activation while increasing the levels, concentra- nanoparticles,1,2 peptide engineering techniques,32 DNA
tions, and releases of several inflammatory mediators, nanocage, and nanoenzymes are reported as the primary
including chemokines, cytokines, and the formation of essential classes of nanoparticles.33 These compounds’
reactive oxygen species (ROS)/reactive nitrogen species nanoscale size and high surface area have given nanopar-
(RNS).12,13 Nanoformulations have also shown the poten- ticles variant physical and chemical properties.
tial to modulate main apoptotic pathways, termed extrinsic Nanotechnology provides preferable drug delivery systems
(death receptor) and intrinsic (mitochondrial-dependent) for enhancing the management of neuronal-related disor-
pathways.14,15 Besides, nanoparticles play essential roles ders via the diagnosis, monitoring, controlling, and repair-
in decreasing the burdens of amyloid-beta (Aβ). Aβ is ing at a molecular level. Treatment with nanoparticles has
formed by the enzymatic degradation of an amyloid pre- shown considerable consequences like suitable biodegrad-
cursor protein (APP) cleaved in a series of stages, resulting ability and biocompatibility, improvement of the therapeu-
in the creation and production of amyloid proteins. An tic efficacy and drug pharmacokinetics, and decreasing
imbalance in the design and subsequent elimination of adverse effects of the drug. Regarding exerting such
Aβ results in the neuronal buildup that could be a precur- effects, nanoparticles modulate major dysregulated path-
sor to some NDDs.8,16 ways of NDDs, including oxidative stress, inflammation,
Consequently, since phytochemicals are potential apoptosis, and proteins aggregation. Such anti-inflamma-
multi-target agents in targeting neuroinflammatory, neu- tory properties are dependent on several factors, including
roapoptotic, neuronal oxidative stress and proteins aggre- nanoparticles’ high surface area to volume ratio, which
gation pathways, they would be potential alternative facilitate the suppressive potential of associated drugs on
therapies in combating NDDs. In this line, targeting the enzymes, cytokines, and other components involved in the
aforementioned pathways by nanoformulations of phyto- inflammatory process.5
chemicals and synthetic drugs1,8,17,18 could open new
roads in combating Alzheimer’s disease (AD),19 Neuronal Oxidative Stress in NDDs: Role
Parkinson’s disease (PD),20,21 amyotrophic lateral disease of Nanoparticles
(ALS),22,23 stroke,24–26 multiple sclerosis (MS),27 and Oxidative stress is usually described as a disparity between
Huntington’s disease (HD).28 antioxidants’ activity and oxidants production leading to
Previous reports have shown the potential of nanofor- undesirable health consequences in humans and showing
mulations against some NDDs, with no focuses on phyto- an undeniable role in the intensification of variant
chemical effects.20,29–31 A recent study highlighted the disorders.34 This process triggers the onset or exacerbation
nanoformulations of limited phytochemicals and some of diseases by inducing DNA, carbohydrates, proteins, and
plant extracts against NDDs with no focus on dysregulated lipids. Cancer, cardiovascular disease, chronic obstructive
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Dovepress Fakhri et al
pulmonary disease, and asthma are related to oxidative Similarly, treating transgenic mice with CeO nanopar-
stress and ROS production. Similarly, there is reliable ticles led to the suppression of progressive left ventricular
evidence that oxidative stress may contribute to various dysfunction and diminished the myocardial oxidative
NDDs like AD, PD, stroke, HD, and ALS. Oxidative stress. It also refused the serum levels of C-reactive pro-
damage to macromolecules is the hallmark of NDDs and tein, monocyte chemoattractant protein 1 (MCP-1), and
accelerates the progression of such disorders. Oxidative total nitrated proteins and the levels and expression of
stress could lead to neuronal cell death and promote toxic tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6,
signalings/cascades. Accordingly, several studies reveal IL-1β, and other pro-inflammatory cytokines in the
the exogenous and endogenous sources of oxidative stress myocardium.40 However, these nanostructures do not
and possible effective mechanisms in controlling those have sufficient therapeutic potential to be used without
pathways.9,35 In addition, protein misfolding plays a pivo- therapeutic options. For this reason, functionalizing these
tal role in generating ROS-induced NDDs. Although redu- nanoparticles by adding the enzymes, natural and synthetic
cing oxidative stress seems to be the essential compounds increases their therapeutic effects. In addition
characteristic of nanoparticles, nanoparticle-related effects to the key enzymatic antioxidant such as glutathione
are contradictory and confusing. The nanoparticles- (GSH) peroxidase, SOD, CAT, other non-enzymatic anti-
induced oxidative stress could be related to the presence oxidants, including GSH, vitamin E, vitamin C, vitamin A,
as well as several phytochemical compounds protect the
of metals, mitochondrial respiration, cell interaction, and
neurons from oxidative stress and show practical advan-
immune cell activation.36
tages in vivo and in vitro. Therefore, applying the supple-
The intrinsic antioxidant properties of nanoparticles are
mental enzymatic to scavenging the free radical is a
not significant, and most of the reported antioxidant effects
rational approach to defend against the neuronal degenera-
have been associated with the loaded antioxidant com-
tion-induced oxidative stress and associated treatment to
pounds. Nanoparticles have increased the bioavailability,
delay or prevent the progression/development of NDDs.
solubility, and BBB permeability of antioxidant com-
Targeting and accurate delivery of antioxidant com-
pounds, enhancing the efficiency and performance of
pounds and enzymes to different body parts, especially
such compounds.2 However, some oxide nanoparticles
the central nervous system (CNS), is another support
exert intrinsic antioxidant activity via triggering antioxi-
mechanism of nanoparticles versus oxidative stress.41,42
dant mediators and scavenging the ROS and RNS. Cerium
Gil et al investigated the in vitro antioxidant and beneficial
oxide (CeO) nanoparticles can appropriately mimic the
effects of nanocrystalline cerium dioxide (CeO2) in elevat-
effects of variant enzymes involved in reducing oxidative
ing CAT and SOD enzymes in conjugation with nanocrys-
stress, such as superoxide dismutase (SOD), catalase
talline CeO2. Results demonstrated that antioxidant
(CAT), and phosphatase. The use of CeO nanoparticles
enzymes combined with nanoceria had shown suitable
seems to be increasing due to such an inherent effect. stability as antioxidant activity synergistically increased.43
CeO nanoparticles are memorable and exciting with Furthermore, Reddy et al attempted to enhance the bioa-
unique properties that have attracted much attention due vailability of SOD by providing a nanoformulation, encap-
to their specific features, including their yummy regenera- sulating SOD in poly(D, L-lactide-co-glycolide)
tive potential and ROS scavenging activity.37 In the study nanoparticles. It led to increased bioavailability, neuropro-
of Caputo et al, the antioxidant potential of CeO nanopar- tection against apoptosis, neurological recovery, and redu-
ticles emphasized that the antioxidant activity of CeO cing the infarct volume, level of ROS, and diminished the
nanoparticles was considerably more than a vitamin E ischemia-reperfusion injury in the rat’s model of focal
analog and N-acetyl-cysteine to diminishing the oxidative cerebral ischemia-reperfusion injury.44 In a similar study,
signal of 2′-7′-Dichlorofluorescein promoted by irradiated a new nanoformulation’s in vitro neuroprotective activity
titanium dioxide (TiO2) nanoparticles.38 In another study, was investigated. Results demonstrated that the intracellu-
Ragg et al reported that manganese oxide nanoparticles lar neuronal uptake of SOD increased when encapsulated
provided an intrinsic SOD-like activity and remarkably in poly(lactic-co-glycolic acid) [PLGA] nanoparticles.
increased the magnetic resonance imaging (MRI) contrast, Additionally, its neuroprotective activity in cultured
making it suitable for the imaging and treating cancer human neurons was enhanced versus the oxidative stress
cells.39 phenomenon.45,46
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Platinum (Pt) is another helpful agent in nanomedical their roles via releasing variant inflammatory mediators,
studies that can catalytically convert O2 to H2O2 and then including cytokines, chemokines, histamines, and leuko-
facilitate the conversion of H2O2 to O2 and H2O. This trienes. Moreover, mast cells promote the allergic inflam-
essential and practical feature of Pt makes it an attractive matory responses by enhancing immunoglobulins E (IgE)
and suitable candidate for modulating oxidative stress synthesis by B-lymphocytes.5
conditions through mimicking the CAT/SOD enzyme Additionally, nuclear factor kappa-light-chain-enhancer
effects.47,48 Moreover, improving the delivery of CAT of activated B cells (NF-κB) signaling is another crucial
via the generation of CAT-loaded nanoparticles provided pathway that can activate and affect more than 500 genes
better in vitro neuroprotective activity against the oxida- involved in the neuroinflammation process. The role of
tive stress induced by H2O2. CAT-loaded nanoparticles NF-κB is critical in regulating neuroinflammation-asso-
decreased H2O2-induced mitochondrial membrane distor- ciated disease pathogenesis.53 Neuroinflammation plays a
tion, DNA damage, cell membrane integrity, and protein major role in fighting the pathogenesis progression of
oxidation.49 Also, Martín et al designed and investigated neurodegenerative and psychiatric disorders which leads
the in vitro antioxidant activity of new Pt and gold nano- to neuronal system damage. It seems that regulation of
particles supported on Fenton-treated diamond nanoparti- neuroinflammation can contribute to suitable attractive
cles (Pt/HO-DNP and Au/HO-DNP). The characterized strategies to prevent, treat, and improve the condition of
structure could cross the cell membrane and exert signifi- patients with psychiatric and NDDs, including AD, PD,
cant biocompatibility and meaningful antioxidant activity stroke, ALS, HD, and MS.
versus ROS-induced cellular oxidative stress in a hepa- Nanoparticles have shown significant anti-inflamma-
toma cell line.50 tory potential in the past few decades. These anti-inflam-
In addition, several studies were performed to investi- matory effects are due to the large ratio of surface area to
gate the beneficial effects and the antioxidant potential of volume, which predisposes nanoparticles to exert more
various types of functionalized nanoparticles. The variant appropriate effects in inhibiting the enzymes, cytokines,
nanoparticles, including silver, gold, iron, copper oxide, and other factors involved in the inflammatory process.
and zinc oxide, exerted significant antioxidant activity. Previously, the in vitro and in vivo anti-inflammatory
Briefly, the considerable role of nanoparticles in the pre- activity of the variant nanoparticles, including gold, cop-
vention and control of oxidative stress in NDDs is not per, silver, selenium, zinc oxide, magnesium oxide, iron
hidden from anyone, and these systems can play a more oxide, and CeO, were reported.5
vital role in various diagnostic and therapeutic stages of Zinc oxide nanoparticles demonstrated anti-inflamma-
NDDs in the future. tory activity via blocking the pro-inflammatory cytokines
such as TNF-α and IL-1β that lead to the downregulation
of inflammatory responses, reducing the proliferation and
Neuroinflammation in NDDs: Role of differentiation of mast cells. Furthermore, zinc oxide nano-
Nanoparticles particles diminished caspase-1 in activated mast cells,
Neuroinflammation is the stimulation and enabling of the suppressed the NF-κB signaling and lipopolysaccharide-
brain’s innate immune system in a complex replication to induced NF-κB as well as reduced the cytosolic degrada-
an inflammatory condition associated with several mole- tion of IκBα, and production of malondialdehyde, IL-1β,
cular and cellular variations within the brain. This TNF-α.5,54,55 Inhibiting the proliferation of mast cells,
response leads to interfering with the activation of glial regulating the level of p53 protein, suppressing the expres-
cells and enhancing the levels, concentration, and release sion of cyclooxygenase (COX-2) and inducible nitric
of variant inflammatory mediators, like chemokines oxide synthase (iNOS) are some of the other anti-inflam-
(CXCL1, CCL5, CCL2), cytokines (TNF-α, IL-6, IL-1β), matories mechanisms of zinc oxide nanoparticles.5
as well as the production of ROS and RNS.13,51 Moreover, Furthermore, gold nanoparticles decrease ROS production,
enhancing the edema, infiltration of peripheral immune diminish the lipopolysaccharide-induced production of
cells, elevating the breakdown, and permeability of the several pro-inflammatory cytokines such as TNF-α, IL-
BBB are also other harmful mechanisms that occur during 17, IL-12, and IL-1β.5,56 Treatment with gold nanoparti-
neuroinflammation.13,52 Mast cells are other parts of the cles led to the modulation of phosphoinositide 3-kinases
inflammatory and immunoregulatory process that exerts (PI3K), mitogen-activated protein kinase (MAPK)

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signaling pathways, and downregulation of pro-inflamma- kinases (JNK), IKK-α/β, signaling pathways as well as
tory cytokines in hepatic stellate and Kupffer cells.5,57 enhanced the activation of AMP-activated protein kinase
Gold nanoparticles also showed the potential of suppres- (AMPK) and nuclear factor-erythroid factor 2-related
sing Aβ aggregation in AD.58 factor 2 (Nrf2), and upregulation of NQO1 and heme
Similarly, silver nanoparticles also showed anti-inflam- oxygenase-1 (HO-1) expression.67 Moreover, synthe-
matory activity via diminishing the expression of hypoxia- sized gold and silver nanoparticles exerted anti-inflam-
inducible factor 1-alpha (HIF-1α), reducing the generation matory and analgesic activities.68
and secretion of several pro-inflammatory cytokines such Similarly, synthesized silver nanoparticles enhanced
as TNF-α, IL-13, IL-12, IL-9, IL-5, and IL-4. Moreover, the anti-inflammatory, antioxidant, anti-diabetes, and anti-
treatment with silver nanoparticles diminished the expres- bacterial activities of some extracts.69 Besides, silver
sion of the COX-2 gene, reduced the mucin hypersecre- nanoparticles produced by plant extracts diminished in
tion, decreased VEGF levels, decreased the levels of vivo carrageenan-induced oxidative stress and inflamma-
VEGF, and suppressed the T helper type-2 cell-mediated tion responses.70 In addition, green synthesis of silver
inflammation.5,59–62 Selenium nanoparticles exert the anti- nanoparticles71,72 and Terminalia species leaves extract73
inflammatory response via suppressing the phosphoryla- showed significant anti-inflammatory activity via reducing
tion of IκB-α, inhibiting the release of NF-κB, and redu- the production of cytokines and inhibiting the cyclooxy-
cing the lipopolysaccharide-induced release of pro- genase enzyme.
inflammatory mediators. Furthermore, the expression of In all, nanoparticles can attenuate several inflammatory
COX-2 and iNOS enzymes was inhibited after treatment pathways and mediators towards combating NDDs.
with selenium nanoparticles.5,63 The fibrinogen into fibrin
converter enzyme, thrombin, can augment the inflamma-
tory response through amplifying the downstream signal-
Neuroapoptosis in NDDs: Role of
ing or mediators via activation of protease-activated Nanoparticles
receptors and enhancing the levels of cytokines and Apoptosis is described as programmed cell death asso-
P-selectin. Previous studies demonstrated that TiO2 nano- ciated with some of the morphological changes, including
particles led to the suppression of the inflammation via the condensation of chromatin, breakdown of the nuclear
increasing levels of the thrombin-antithrombin complex, membrane, cell shrinkage, and the production of apoptotic
thrombin inactivation, and suppressing the protease-acti- bodies. Two main pathways that trigger the apoptosis
vated receptor’s pathway.5,64 Also, CeO nanoparticles process are extrinsic that commonly known as the death
decreased the inflammatory response, neuronal death, receptor pathway, and mitochondrial or the intrinsic
microglial activation, oxidative stress, reduced TNF-α, pathway.14 The intrinsic pathway of apoptosis is started
and neurodegenerative events in the rat’s model of retinal within the cell, which leads to increasing the activation
neurodegeneration.65 and expression of BH3-only proteins, consequences in the
Besides, green synthesized nanoparticles showed activation of the Bax. In some cells, this process may be
more significant anti-inflammatory effects. The gold accompanied by Bak elevation that enhances the formation
nanoparticles synthesized from some plants showed sig- of mitochondrial membrane pores’ construction and facil-
nificant neuroprotective activity via enhancing motor itates the releasing and extrication of cytochrome c to bind
coordination and diminishing the neuroinflammation in apoptotic peptidase activating factor-1 (APAF-1). Caspase
vitro and in vivo models of PD.66 In a similar study, activation results from this cascade that enhances cleave
Park et al investigated the anti-neuroinflammatory activ- and activates the downstream caspases and cellular protein
ity of the gold nanoparticles capped with plant extracts. degradation.14 The external pathway starts outside the cell
Synthesized gold nanoparticles showed anti-neuroin- and is triggered via the activation of death receptors by
flammatory effects via diminishing the levels and activ- death ligands and activates caspase-8 and leads to cleaves
ity of pro-neuroinflammatory cytokines and mediators, downstream caspases as well as cleaves and facilitates the
decreasing the production of ROS, downregulation of activation of the BH3-only protein Bid.14 Inhibiting var-
p38MAPK, NF-κB, extracellular signal-regulated kinase iant parts of the intrinsic and extrinsic apoptosis pathways
(ERK-1/2), Janus kinase (JAK)-signal transducer and can lead to significant effects and is considered a promis-
activator of transcription (STAT), c-Jun N-terminal ing strategy for suppressing neuronal apoptosis.

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Despite these applications, nanoparticles have been significant part of brain plaques/tau protein and a central
used in several studies to enhance various compounds’ in component of neurofibrillary tangles.80 In afflicted
vitro and in vivo neuroprotective properties. Such technol- families with genetic anomalies, mutations and multiplica-
ogy has effectively reduced neuronal inflammation, oxida- tions of α-synuclein and Aβ-related genes produce some
tive stress, and apoptosis.1 Accordingly, Wang et al kinds of NDDs. Overproduction of such proteins and their
designed a new nanoparticle-mediated formulation to excessive aggregation has been proven in various models
improve the drug delivery for protecting neurons against to neuronal malfunction and death.81 Neurofibrillary tan-
injury induced by cerebral ischemia/reperfusion. gles are composed of intraneuronal paired helical filaments
Nanoparticles loaded with complement components sig- of a microtubule-associated protein (tau) that has been
nificantly diminished the microglial neurotoxicity after hyper-phosphorylated at several locations throughout the
injury via decreasing the levels and activity of pro-inflam- polypeptide chain.
matory factors, inflammatory cells, and neuronal On the other hand, amyloid plaques are extracellular
apoptosis.74 In the study of Yuan et al, treatment with aggregates whose major component is an amyloid peptide
selenium nanoparticles provided significant neuroprotec- (Aβ40–42). These amyloid plaques arise when Aβ aggre-
tive activity via diminishing the oxidative, inflammatory, gates, thereby generating oligomers, protofibrils, and
and apoptotic cascade. fibrils that are deposited in the brain.3 The primary peptide
Moreover, selenium nanoparticles properly reversed in the brain parenchyma is the Aβ1-42 peptide, which is
the neurochemical alterations, neuronal loss, and oxidative sensitive to aggregation/fibrillation, is thought to undergo
damage in the mice model.75 In another study, antioxidant metal-induced aggregation response, and finally produces
enzymes-loaded nanoparticles protected the neuronal cell plaques. In this way, nanoparticles play an important role
against apoptosis via declining mitochondrial dysfunction with their anti-amyloid properties.3
in the rat model of spinal cord injury. The treatment with AD is considered a common form of dementia char-
encapsulated CAT and SOD in biodegradable nanoparti- acterized by memory loss, cognitive impairment, and
cles improved mitochondrial function, decreased cyto- behavioral problems. AD is a protein misfolding-based
chrome c activities, and inhibited the activation of disorder caused by the aggregation and misfolding of tau
caspase-3 and cleaved caspase-3, ROS concentration, and and Aβ peptides, leading to neurofibrillary tangles and
neuronal activity cell apoptosis as well as lesser affected amyloid plaques, respectively.82,83 The results of two
area compared to untreated animals.76 Furthermore, the sequential cleavages of amyloid precursor protein are a
combination treatment with gold nanoparticles reduced transmembrane protein with 42-residue known as Aβ that
brain cell apoptosis and brain infarct volume. It enhanced does not play a specific physiological role.82,83 Increased
the levels and concentration of several neurotrophic fac- concentration of immature autophagic vacuoles in neurons
tors in the rats model of ischemic stroke.77 Also, using is associated with elevating the production of autophagic
biodegradable nanoparticles diminished the edema forma- core agents, spoiled fusion with lysosomes, and retrograde
tion, inflammatory responses, neuronal apoptosis and pro- transportation of autophagosomes that facilitate the accu-
moted the process of neurogenesis in infarcted rat brain.78 mulation of pathogenic Aβ.82 Tau phosphorylation, located
Accordingly, boron nitride nanoparticles provided signifi- primarily in neurofibrillary tangles, is another hallmark of
cant neuroprotective effects versus the MPP+ induced neu- AD.82,84
ronal apoptosis in the in vitro model of PD.79 Further, a mutant form of the nerve terminal protein, α-
Thus, multiple apoptotic mediators are modulated by synuclein, is a significant pathogen of PD. The function of
nanoparticles in fighting NDDs. mutant α-synuclein as the main autosomal dominant pro-
moted several point mutations accompanying the PD (eg,
E46K, A30P, and A53T) that lead to rendering the aggre-
Protein’s Aggregation in NDDs: Role of gation and misfolding of α-synuclein prone. The formation
Nanoparticles and development of intracellular inclusions named Lewy
Protein and peptide aggregation into amyloid fibrils has bodies (LBs) result from aggregation and accumulation of
been identified as a key cause of various protein misfold- mutant α-synuclein that are a hallmark of familial and
ing-related disorders, including AD, PD, ALS, and mis- sporadic PD.82,85,86 ALS is another debilitating neurode-
cellaneous NDDs.3 Researchers discovered Aβ as the generative disease that loses neurons responsible for

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controlling voluntary muscles. Signs and symptoms play a arimoclomol, nuedexta, AADvac1, and TRx0237, targets
significant role in diagnosing a person and tests that elim- this protein.92
inate other possible reasons. It was reported that mutations Dysregulated signaling pathways in NDDs are pre-
in the chromosome encoding SOD, chromosome 21, have sented in Figure 1. Besides, the role of nanoparticles in
been implicated as a major cause in 2% of all cases and combating NDDs-associated neuroinflammation, neuronal
20% of familial cases with ALS.82 Over one hundred oxidative stress, neuroapoptosis and protein aggregation is
diverse mutations have been identified with this mutation, provided in Figure 2.
which is thought to be transmitted autosomal dominantly.
Mutation of the SOD1 gene is the most common cause of Dual Function of Nanoparticles;
ALS, frequently occurring in North America; this level of
Neurotoxicity Potential of
mutation is characterized by an exceptionally rapid onset
and progression of the disease. Scandinavians are more
Nanoparticles via Induction of
likely to have the mutation D90A-SOD1 than people liv- Apoptosis, Oxidative Stress, and
ing with typical ALS. It is more slowly progressing than Inflammation
typical ALS, and people with this mutation live an average As mentioned, nanoparticles have shown significant bene-
of 11 more years.87–89 In addition to the SOD1, vesicle- ficial activities and promoted increasing effects, bioavail-
associated protein B (VAPB), tank binding kinase 1 ability, half-life, stability against degradation in the CNS.
(TBK1), Ubiquilin-2, tar DNA binding protein-43 (TDP- Such effects enhance the efficacy, reduce dosage and side
43), valosin containing protein (VCP), p62, and fused in effects of these structures in the treatment of NDDs.1,31
sarcoma (FUS) are other misfolded proteins involve in Despite these practical effects, nanoparticles have also
pathologically of ALS.90,91 shown a severe triggering effect on inflammation, apopto-
In addition, tau protein, huntingtin with tandem gluta- sis, necrosis, autophagy, and oxidative stress processes,
mine repeats, prion proteins, and transthyretin (mutant which may promote the potential of chronic and acute
forms) are other essential aggregated proteins related and human health risks95; however, the systematic clinical
associated with several neurodegenerative diseases includ- studies and detailed documented reports that nanoparti-
ing multiple neurodegenerative disease tauopathies, HD, cle-induced toxicity in humans is limited. Several studies
spongiform encephalopathies, and familial amyloidotic analyzed the toxicity potentials of nanoparticles in animal
polyneuropathy, respectively.82,92 Misfolded disease pro- models and cell culture.96 Therefore, increasing our under-
teins exert toxic effects by interfering with several path- standing and knowledge of the toxicity mechanisms of
ways and strongly binding to the biological membranes, these structures is essential and helps to provide new
such as mitochondrial membranes, plasma, and other cyto- strategies for designing, producing, and utilizing suitable
solic protein membranes.92,93 This process results in the nanoparticles for safer use of nanotechnology in humans.95
distortion and loss of membrane integrity and leads to Neurotoxicity, pulmonary toxicity, genotoxicity, and
ROS production, Ca2+ influx aberrant, and the alteration immunotoxicity are some of the most important examples
of variant signaling pathways, which facilitated cell of reported human toxicity induced by nanoparticles.95
death.92,93 For instance, mutant tau disrupts neuronal The nanoparticle-induced toxicity may be related to
transport mechanisms and microtubule function, and α- dosage, frequency of use, concentration, and time of expo-
synuclein, tau, and Aβ lead to interference with synaptic sure, as well as the routes of administration.95 Also, shape,
signaling. Moreover, mitochondrial protein transport dis- particle size, charge, roughness, surface coating, and com-
ruption is another α-synuclein toxicity mechanism. The position are other parameters that affect nanoparticles
nucleocytoplasmic transport of proteins and RNA has toxicity.97 The production of variant ROS including hydro-
also been disrupted by cytosolic aggregates of several xyl radicals, singlet oxygen, peroxide ions, oxygen radi-
other proteins, including mutant huntingtin, artificial β- cals, superoxide anion radicals, and hydrogen peroxide
sheets, and TDP-43.92–94 Targeting these proteins can be (H2O2) was introduced as the main nanotoxicity mechan-
a valuable and significant strategy for preventing and ism that may occur in various ways.95,98 ROS generation,
treating neurodegenerative diseases. Various drugs have inducing oxidative stress, membrane perturbation, DNA
been approved or investigated in different phases of clin- damage, cytoskeletal dysfunction, direct physical damage,
ical studies, including istradefylline, deferiprone, enzyme dysfunction, blocking the cell membrane channels

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Figure 1 Dysregulated signaling pathways in NDDs.

Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; Cyt c, cytochrome c; ERK, extracellular signal-regulated kinase; HD, Huntington’s disease;
iNOS, inducible nitric oxide synthase; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-
chain-enhancer of activated B cells; PD, Parkinson’s disease; PI3K, phosphoinositide 3-kinases; RNS, reactive nitrogen species; ROS, reactive oxygen species; STAT, signal
transducer and activator of transcription.
and receptors, abnormal morphological stretching, and cause influence cell survival, proliferation, and
protein misfolding were reported as the main toxicity differentiation.95,103
mechanism of nanoparticles.97–100 The oxidative reaction Several other studies have investigated the neurotoxi-
of an electron with nanoparticle’s surface groups or transi- city of various nanostructures. The intravenous injection of
tion metals is another reported mechanism of ROS produc- polysorbate 80-modified chitosan nanoparticles leads to
tion. Enhancing the surface area leads to an augmentation the accumulation of nanoparticles in the cerebellum, fron-
of chemical reactivity potentially and ROS production. tal cortex, oxidative stress elevation, inflammatory process
Nanoparticles can promote mitochondrial membrane activation, and neuronal apoptosis in treated rats.104
damages. Moreover, it was reported that direct administration of
For this reason, mitochondrial respiration and pene- the liposomal formulation of cisplatin into the brain
tration of ROS from perforated mitochondrial mem- might lead to highly neurotoxic advantages due to the
branes into the cytoplasm is another mechanism of intrinsic neurotoxic effects of liposomes in combination
ROS production.95,101,102 The elevated intracellular with cisplatin.105 Also, exposure to the polyamidoamine
ROS levels lead to more ROS releases from mitochon- dendrimers provided a charge surface-dependent in vitro
dria and amplify the oxidative imbalance and oxidative neurotoxic activity and increased the DNA damage, apop-
stress that promoted damage to the DNA, cellular orga- tosis, oxidative stress, and suppressed neuronal differentia-
nelles, ion channels, receptors, and cell membranes, tion and mitochondrial function in neural cells.106
which accelerate more adverse effects and toxicity.95 Treatment with iron oxide nanoparticles prompted oxida-
In addition, released harmful metal ions and ROS can tive stress, enhanced iron accumulation, and facilitated
interfere with variant signaling pathways including pro- protein aggregation in the neural cells.107 Also, induction
tein kinase B (Akt), Src, MAPK, NF-κB, and HIF that of oxidative stress was reported as the primary

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Figure 2 The role of nanoparticles in combating NDDs-associated neuroinflammation, neuronal oxidative stress, and neuroapoptosis.
Abbreviations: Ag, silver; AMPK, AMP-activated protein kinase; ARE, antioxidant response element; Au, gold; CAT, catalase; CeO, cerium oxide; CeO2, cerium dioxide;
COX, cyclooxygenase; Cu, copper; ERK, extracellular signal-regulated kinase; Fe2O3, Iron oxide; IL, interleukin; iNOS, inducible nitric oxide synthase; JAK, Janus kinase;
MAPK, mitogen-activated protein kinase; MgO, magnesium oxide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NPs, nanoparticles; Nrf2, nuclear
factor-erythroid factor 2-related factor 2; PI3K, phosphoinositide 3-kinases; PLGA, poly(lactic-co-glycolic acid); Pt, platinum; RNS, reactive nitrogen species; ROS, reactive
oxygen species; Se, selenium; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TiO2, titanium dioxide; TNF-α, tumor necrosis factor-alpha;
ZnO, zinc oxide.
neurotoxicity mechanism of silver nanoparticles in the the potential of treatment tools for NDDs. It makes the
exposed rat’s cerebral astrocytes.108 Furthermore, the in BBB one of the main limitations of progress in the treat-
vivo and in vitro investigation of neurotoxicity mechan- ment of NDDs. The BBB is composed of an evolved from
isms of silica nanoparticles showed the induction of neu- the brain microvascular system, which acts as an effective
ropathology, MAPK activation, and behavior changes in membrane barrier that separates circulating blood from the
mice and cultured neurons.109 Silica and gold nanoparti- brain’s extracellular fluid in most vertebrate species.114–117
cles also represent a new class of delivery systems to The BBB consists of the basal lamina, which comprises
multi-drug resistance into neurons to treat future brain various extracellular matrix proteins, including collagen,
disease.110 Oxidative stress, genotoxicity, inflammatory heparan sulfate, and laminin that surround pericytes and
response, apoptosis, dysregulation of neurotransmitters, microvessel endothelial cells.114,116 Astrocyte endfeet and
and to a lesser extent, DNA methylation and autophagy interneurons are other structures present in the construc-
have been considered possible neurotoxicity mechanisms tion of BBB. The BBB already contains gap junctions,
of TiO2 nanoparticles.111 Cadmium telluride quantum dots tight junctions, and adherens junctions. Still, tight junc-
exerted neurotoxicity effects on motor neurons via induc- tions appear to be more important than the other types of
tion of oxidative stress.112 Moreover, acceleration of connections in the BBB because they cause high levels of
autophagy process, elevating levels of cytoplasmic Ca2+, electrical resistance between the endothelial cells.114,115
and impairments of synaptic transmission are reported as
The prominent role of BBB is the protection of the brain
the primary other in vivo and in vitro neurotoxicity
from all foreign agents. BBB also supported the brain from
mechanisms of the quantum dot.113
alterations of ionic composition in the cerebrospinal fluid
and facilitated the metabolizing of variant chemical com-
Overcoming the BBB by pounds and disposing of waste products.115,116 The disrup-
Nanoparticles, as an Attractive, and tion of the extracellular matrix proteins can increase the
Effective Strategy BBB permeability, which assists and improves the drug’s
The inability of most therapeutic compounds to suffi- transportation. Nanoparticles generally cross the BBB
ciently cross the blood–brain barrier (BBB) diminishes through two mechanisms, including passive and active

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transfer pathways. Accordingly, gold nanoparticles and problems. The brains of AD patients show the existence of
small lipophilic molecules (<400 Da) could pass through extracellular Aβ plaques and intraneuronal tau-containing
the BBB in a passive transfer system.115,116,118 In addition, neurofibrillary tangles cross-talked to inflammatory/oxida-
active endocytosis is mediated by receptor, carrier, and tive stress/apoptotic pathways.124 The presence of BBB is
adsorption strategies. Receptor-mediated endocytosis a critical issue in the treatment of neurological disorders
facilitates the penetration of various nanostructures such because it prevents many medicines from entering the
as liposomes and PLGA based nanoparticles from brain in adequate concentration.19 So, we need nanomedi-
BBB.116,119,120 The receptors responsible for active influ- cine therapy to overcome such issues.
ence include low-density lipoproteins, transferrin, lactofer-
rin, insulin receptors, and their ligands.115–117 The process Alzheimer’s Disease and Phytochemicals
of nanoparticles transportation by adsorption to endothelial Nanoformulations
cells is mediated by the surface properties of the nanopar- The plant kingdom and associated phytochemicals have
ticles. As the plasma membrane of endothelial cells is shown promising anti-AD effects.10 As a natural polyphe-
negatively charged, the cationic nanoparticles are more nolic compound, resveratrol is found in grapes, mulberries,
likely to undergo this mechanism than negatively charged peanuts, rhubarb, and wines. It has been shown to depo-
or neutral ones. Liposomes and gold nanoparticles can lymerize Aβ peptides via a proteasome function; however,
cross the BBB using such method.116 An additional it does not impact β- and γ-secretase enzymes and trans-
mechanism of nanoparticles for enhancing drug delivery thyretin, a sequesters protein amyloid protein. Several
across the BBB is carrier-mediated transport pathways findings showed the potential of resveratrol against tauo-
such as the glucose transporter 1 (GLUT1) protein and pathy associated with AD, demonstrating a decrease in tau
the amino acid transporter (ASCT2).116 levels in rats and suppression of tau hyperphosphorylation/
accumulation.121 However, there are some pharmacoki-
Nanoformulations in Combating netic limitations in its application.125 Considering the
resveratrol’s quick clearance from the bloodstream, solid
Neurodegeneration: Pre-Clinical
lipid nanoparticles (SLNs) were designed to encapsulate
Evidence and carry the extracts into the brain, where amyloid fibril
Pharmaceutical studies have recently concentrated on
production occurs. SLNs are a viable, dynamic mechanism
advancing nanotechnology methods relevant in several
for delivering resveratrol to the brain in an area and avert/
medicine sectors, including drug delivery.31 As a result,
slow AD development by inhibiting the production of Aβ
it is necessary to develop novel ways to enhance the
(1–42) aggregates.126 Also, the in vivo evaluation showed
effectiveness, transport throughout the BBB, bioavailabil-
that designed nanostructured lipid carriers (NLCs), deliv-
ity, and ultimately the negative impact of pharmacological
ered nasally, may successfully combat AD compared to an
substances used to treat NDDs.121 Applying nanoparticles
orally supplied resveratrol solution. The better memory
to transport therapeutic substances enhances biodistribu-
function and enhanced permeation across nasal mucosa
tion and pharmacokinetics, permits co-delivery of several
recommend that the resveratrol NLC-based in situ gel
drugs, provides targeted intracellular drug delivery and
could efficiently decrease the crystallinity of particles
decreases systemic toxicity/side effects.122
through the lipid-oil mixture and convenient strategy for
the treatment of AD.127
Alzheimer’s Disease and As another phenolic compound, curcumin, which is
Nanoformulation gained from Curcuma longa, has beneficial effects in
AD is the primary cause of dementia, a clinical condition treating NDDs; however, low bioavailability, a fast meta-
marked by a gradual decrease in two or more general bolism, and quick elimination of curcumin limited its
cognitive, such as dysfunctionalities in cognition, lan- efficacy.128 Curcumin’s primary product, responsible for
guage, executive/visuospatial activity, personality and its neurotherapeutic effectiveness, exerts through a
behavior, resulting in a loss of ability to execute instru- decrease in Aβ peptide aggregation. It also reduced Aβ-
mental and/or fundamental activities, and the most com- induced oxidative damage and neuroinflammation by
mon neurodegenerative condition.123 It is generally using nanoformulation. Continuously, nanocurcumin pre-
diagnosed after 3–6 years of amnestic moderate cognitive vented the formation and neurotoxicity of two AD

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markers, hyperphosphorylated tau and amyloid patients and mice following treatment with
misfolding.129 Furthermore, it controls several aspects of nanoliposomes.135 Curcumin can bind tau protein-based
the AD, such as binding copper, decreasing cholesterol amyloid by in vivo and in vitro models of AD. It exhibited
levels, regulating microglial function, inhibiting acetylcho- anti-amyloid effects at micromolar doses. Curcumin was
linesterase, upregulating the insulin signaling pathway, and also found to be capable of inhibiting tau protein hyper-
acting as an antioxidant.130 Even at modest doses, nano- phosphorylation. Curcumin-encapsulated PLGA nanopar-
curcumin improved working and recall memory in a mice ticles could eliminate amyloid aggregates, thereby
AD model. Besides, curcumin bioavailability was consid- showing antioxidative, with no cytotoxic effect.3
erably enhanced by the nanoparticle formulation, accord- Naringenin is a flavonoid that protects neurons from
ing to pharmacokinetic tests.129 free radicals and inflammation but has a poor capacity to
Using curcumin nanoformulation also increased its penetrate biomembranes. The naringenin-loaded nanoe-
solubility and stability, propelling it to the forefront of mulsion significantly decreased the direct toxic effect of
medicinal uses. Additionally, nanocurcumin nanoparticles Aβ on SH-SY5Y cells, which was linked with a decrease
are more stable than native curcumin under physiological in the expression of APP, β-secretase, and attenuating
circumstances. Accordingly, PLGA-nanoparticles offered amyloidogenesis. In SH-SY5Y cells exposed to Aβ, it
an effective curcumin delivery method to defend human also reduced the amounts of phosphorylated tau. These
neuronal cells from oxidative damage, as shown in AD.131 findings implied that naringenin-loaded nanoemulsion
Curcumin encapsulated in PLGA nanoparticles with a might be a potential method for treating AD.136
ligand for BBB crossing demonstrates minimal toxicity As another phytochemical, quercetin has shown poten-
and a substantial reduction in Aβ aggregates. tial therapeutic roles against NDDs. The limited oral bioa-
Consequently, brain administration of nanocurcumin vailability of quercetin restricted its medicinal use. As a
through BBB crossing is a potential future strategy in possible oral therapy for AD, nanoencapsulated quercetin
treating AD.132 in zein nanoparticles dramatically increased oral absorp-
Curcumin-encapsulated in PLGA (Cur-PLGA) nano- tion and bioavailability of the flavonoid. Treatment with
particles, particularly compared to bulk curcumin, pro- such orally used flavonoid enhanced the cognitive and
moted proliferation of endogenous neural stem cells and memory deficits of SAMP8 mice.137 When quercetin was
neuronal differentiation in vitro and in the hippocampus incorporated into -cyclodextrin-dodecyl carbonate nano-
and subventricular zone in vivo. Curcumin nanoparticles particles, its anti-inflammatory actions via diminishing
stimulate proliferation at smaller concentrations and are the toll-like receptor 4 (TLR4) and COX-2 signaling path-
not toxic at high doses. In an AD rat model, Cur-PLGA way on SH-SY5Y cells were increased compared to cells
nanoparticles restored mediated inhibition on hippocam- treated with free quercetin. The objective of encapsulating
pus neurogenesis, cognition, and memory via activating quercetin in nanoparticles was to enhance its penetration
the canonical Wnt/β-catenin pathway.133 For the treatment through the BBB and bioavailability, preventing or decel-
of AD, PLGA-poly(ethylene glycol) (PLGA-PEG) conju- erating the progression of AD.138 Palle and Neerati also
gated with B6 peptide-loaded with curcumin (PLGA-PEG- showed that pretreatment of rats with quercetin nanoparti-
B6/Curcumin) might be a viable option in vitro through cles reduced scopolamine-induced behavioral alterations,
reducing curcumin size, enhancing its cellular absorption, suggesting that it might be used as a preventative approach
and also blood compatibility. The results showed a signifi- against the advancement of AD. In such experimental
cant increase in spatial learning and memory performance models, quercetin nanoparticles outperformed quercetin,
of APP/PS1 mice compared to native curcumin. Besides, implying that the enhanced effectiveness is related to a
ex vivo studies revealed that PLGA-PEG-B6/Curcumin more extended residence period in the systemic circulation
decreased hippocampus Aβ production and deposit, as and higher bioavailability.139
well as tau hyperphosphorylation.134 The genesis of AD has been linked to the dysfunctional
As another novel formulation of curcumin, nanolipo- interaction of Aβ with excess metal ions. As a result,
somes were found to be stable and monodispersed. Those employing nanoparticles to disturb these metal-peptide
formulations were safe in vitro, inhibited amyloid peptide connections holds much potential as a treatment method.
production, and partly reduced Aβ-induced toxicity. They In vitro investigations showed that PLGA-functionalized
found deposits in post-mortem brain tissue from AD quercetin nanoparticles have minimal cytotoxicity and,

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therefore, can prevent the neurotoxicity of the Zn2+-Aβ42 comparable to the rivastigmine impacts. Our findings
system while also increasing neuron cell survival by sup- showed that putting sesamol in the SLNs is an excellent
pressing the Zn2+-Aβ42 system. Administration of PLGA- approach for reducing intracerebroventricular streptozoto-
functionalized quercetin nanoparticles in APP/PS1 mice cin-induced neuronal malfunction and memory impair-
improved cognitive functions and memory, according to ments by lowering oxidative stress.146 Sesamol is an
data from in vivo investigations.140 antioxidant-rich substance derived from the oil of
Polyacrylamide-chitosan-PLGA nanoparticles with Sesamum species that may play a preventive function in
CRM197 and apolipoprotein E (ApoE) nanoparticles age-related NDDs such as AD. SLNs are excellent deliv-
were created to slow the degeneration of Aβ-insulted neu- ery vehicles for transporting sesamol to the CNS; they can
rons, improve rosmarinic acid transportation throughout be investigated as a brain targeting approach for AD.
the BBB, and boost antiapoptotic impact via blocking the SLNs were found to successfully repair cognitive impair-
production of caspase-3 and c-Jun parameters on SK-N- ments in rats given intracerebroventricular streptozotocin,
MC cells. Such nanoparticles have the potential to be an as well as alleviating oxidative stress measures including
important route of administration for brain-targeting beha- nitro-oxidative stress and cytokine production in an in vivo
vior and have neuronal restoration in AD therapy.141 research on AD-induced model.124 As another phenolic
The antioxidant effects of epigallocatechin 3-gallate compound, ferulic acid showed high antioxidant action
(EGCG), the main catechin found in tea, are well docu- against AD. Pure SLN demonstrated zero toxicity on
mented. It can enhance the non-amyloidogenic processing human neuroblastoma cells (LAN 5) at the doses tested,
of APP via increasing the expression of α-secretase, there- as well as the capacity to enter these cells. Furthermore,
fore reducing the development of brain Aβ plaques, a cells treated with ferulic acid-loaded SLN produced less
characteristic of AD pathogenesis. The potential of ROS than those treated with free ferulic acid.149
EGCG nanolipidic particles enhanced neuronal α-secretase In addition to the phenolic compounds, alkaloids are
in vitro by up to 91% and its oral bioavailability in vivo by another class of phytochemicals whose nanoformulations
more than two-fold over free EGCG.142 Anti-amyloido- have shown hopeful neuroprotective effects. Berberine is
genic, metal chelation, and antioxidant activities of EGCG an isoquinoline alkaloid used to manage NDDs, especially
have been demonstrated. NanoEGCG antioxidant and dementia, for centuries.147 Berberine-loaded multiwalled
metal chelation capabilities outperformed its free form carbon nanotubes are a tremendous nanostructured con-
and significantly reduced cellular toxicity. struct for delivering berberine throughout the BBB.
Furthermore, an in vitro study demonstrated that Furthermore, the phospholipid-coated and polysorbate-
EGCG nanoparticles could prevent Al3+-induced Aβ42 coated multiwalled carbon nanotubes demonstrated excel-
fibrillation and neurotoxicity.143 In another study, EGCG lent memory function recovery in line with the capacity
was bonded to the surface of selenium nanoparticles to for transferring neuropharmaceutical agents to brain
decrease the cytotoxicity of EGCG at significant concen- microglial cells. The ability of these nanotubes to maintain
trations. EGCG-selenium nanoparticles were synthesized, normal biochemical levels in brain tissue indicated their
given the affinity of peptide to neurons, due to the poor promise for decreasing Aβ-induced AD.148
delivery efficiency of EGCG-selenium nanoparticles to the In addition to phenolic compounds and alkaloids, ter-
targeted cells. The role of selenoprotein in antioxidation penoids are also promising candidates against NDDs. A
and neuroprotection is essential in limiting the initiation sesquiterpene huperzine A (HupA)-loaded, mucoadhesive,
and progression of AD. EGCG-stabilized selenium nano- and targeted PLGA nanoparticles with surface modifica-
particles coated with peptides inhibited Aβ fibrillation and tion by lactoferrin-conjugated N-trimethylated chitosan
efficiently disaggregated Aβ fibrils into harmless aggre- nanoparticles are used for effective intranasal transport of
gates. Furthermore, EGCG-selenium nanoparticles showed huperzine A to the brain for the treatment of AD. The
a strong affinity for labeling Aβ fibrils.144 significant mucoadhesion of such nanoparticles was shown
Sesamol, a polyphenolic substance, is the main com- by in vitro mucin adsorption. The regulated drug release
ponent of sesame seed oil (Sesamum indicum L).145 When was validated by ex vivo drug release and cell survival
the pure sesamol and sesamol-SLN groups were com- tests utilizing the 16HBE cell line. Thus, the active target-
pared, the latter group was much more effective than the ing of lactoferrin and the mucoadhesion of trimethylated
pure sesamol group at 16 mg/kg dosage, which was nearly chitosan nanoparticles were widely dispersed in the brain

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over a long time.149 As triterpenoids, ginsenosides are neuronal cells (higher neuronal counts in hippocampus sub-
other phytochemicals with neuroprotective mechanisms. regions) and decrease of tau hyperphosphorylation in an AD
A new nanotherapeutic approach that increases ginseno- rat model.
side distribution to the brain by boosting BBB permeabil- According to the findings, the liposomes formulation of
ity might aid neuroprotective effects and minimize the rivastigmine (an acetylcholinesterase inhibitor) contributed
formation of Aβ plaques and eventual neurodegeneration. to quicker memory recovery and improved metabolic
For the diagnosis and treatment of AD, PLGA-ginsenoside abnormalities in AlCl3-treated rats. The rivastigmine lipo-
Rg3 nanoparticles offered an intriguing novel theranostic somes nano-based formulation outperformed traditional
material suitable of encapsulating natural nutraceuticals.150 drug solutions in terms of sustained release and patient
Therefore, the nanoformulations of phytochemicals compliance, suggesting it to be a promising drug delivery
(eg, resveratrol, curcumin, naringenin, quercetin, rosmari- method for treating AD.152 Another research showed that
nic acid, EGCG, ginsenoside, ferulic acid, berberine, rivastigmine SLN, while lipidic, demonstrated more drug
huperzine, and sesamol) of different classes (eg, phenolic diffusion than a drug solution containing a crystalline form
compounds, alkaloids, and terpenoids) have shown thera- of the drug. Rivastigmine SLN did not affect nasociliary
peutic effects on AD by modulating multiple dysregulated disruption or cell necrosis, showing that it is acceptable for
pathways. In this line, nanophytochemicals critically inhi- nasal administration.153 The liposomal preparation of
bit the aggregation and production of protein misfolding, donepezil (another acetylcholinesterase inhibitor), a proto-
modulate neuroinflammatory, neuroapoptosis, and neuro- type anti-AD medication, was resilient and exhibited sus-
nal oxidative stress. Additionally, nanophytochemicals tained-release characteristics. Compared to the traditional
improve the bioavailability of secondary metabolites and dose form and method of administration, intranasal deliv-
reduce cellular toxicity by affecting the pathways men- ery of donepezil liposomes dramatically improved the
tioned above. drug’s brain bioavailability. Furthermore, this method
allows patients to self-administer medications painlessly
Alzheimer Disease and Nanoformulations of and simply.154 Continuing to the drugs of this class, galan-
Synthetic Drugs tamine hydrobromide, an acetylcholinesterase inhibitor,
Several synthetic formulations are employed in combating poorly penetrates the brain. To solve these constraints,
AD; however, nanoformulations seem to increase their effi- the SLN formulation of galantamine hydrobromide was
cacy. As a hematopoietic factor, erythropoietin (EPO) is a created. In vivo tests revealed substantial memory restora-
potential neuroprotective agent in AD by promoting neuro- tion potential in cognitive deficit rats compared to an
nal survival and controlling neurogenesis. However, the uninformed medication; SLN provided the bioavailability
transfer of EPO to the CNS is complicated and occurs at of the standard medicines.155
deficient levels because of its large molecular weight, Memantine (an NMDA blocker), authorized for AD
hydrophilicity, and fast blood elimination. This way, Dara treatment, was incorporated into biodegradable PLGA
et al created EPO-loaded SLN to alleviate the restrictions nanoparticles generated using a double emulsion technique
mentioned above.151 In vivo studies showed that EPO-SLN and had a PEG surface coating to target the BBB when
could protect the animals’ brains from damage caused by an taken orally. The in vitro and in vivo data for brain drug
intra-hippocampal injection, with spatial recognition mem- levels revealed that the devised methods transport the
ory considerably recovered compared to rats treated with medication to the target tissue throughout time and the
free EPO. Another synthetic drug, nicotinamide, a histone decrease of Aβ plaques.156 Endogenous estrogen defi-
deacetylase blocker demonstrated in preclinical trials to be ciency following menopause has been linked to the devel-
beneficial in stopping AD, has poor absorption. This hydro- opment of AD in postmenopausal women.157 In an
philic medication was encapsulated in SLN, who functio- ovariectomized rat AD model, orally given tween 80-
nalized the nanocarriers using polysorbate 80, coated PLGA nanoparticles carrying estradiol resulted in
phosphatidylserine, or phosphatidic acid.151 When com- substantially greater brain estradiol levels after 24 hours
pared to traditional oral nicotinamide, the phosphatidylser- than unmodified ones.158
ine-SLN was efficient in conveying and distributing Tarenflurbil is an Aβ42 selective reducing agent, and
nicotinamide to the brain in a sustained manner, supposed the γ-secretase modulator demonstrated encouraging out-
to lead to cognition enhancement, protection of more comes in vitro and in vivo. A Phase II clinical study on

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210 patients with mild AD found that the drug was well Parkinson’s Disease and Phytochemicals
tolerated, with improved performance decline in primary Nanoformulations
endpoints.159 Tarenflurbil’s limited brain penetration was We have previously introduced several phytochemicals in
one of the chief factors for its defeat in Phase III clinical combating PD.163 Resveratrol nanoparticles can sustain
studies on Alzheimer’s patients. As a result, there is an their blood levels for a longer time, improving bioavail-
urgent need to create effective Tarenflurbil delivery meth- ability and, thus, pharmacological impact. As a result,
ods. It was loaded into two types of nanocarriers, PLGA resveratrol nanoparticles were shown to be more effective
nanoparticles, and SLNs. Such nanoparticles demonstrated than naïve resveratrol in dampening rotenone-induced PD-
acceptable brain biodistribution patterns. The pharmacoki- like behavioral abnormalities, biochemical and histological
netic behavior was enhanced by using nanoparticles rather changes, oxidative stress induced by hydrogen peroxide,
than solution/suspension.160 and mitochondrial dysfunction induced by rotenone and
For transport via the BBB, n-butyl-cyanoacrylate saved the functions of complex-I and tricarboxylic acid
nanoparticles can be utilized to contain clioquinol, a enzymes in rats.164
quinolone derivative capable of solubilizing plaques Resveratrol is severely hampered by the BBB, which
that develop in the neocortex in extracellular synaptic restricts resveratrol’s entry to the CNS. In vitro, magnetic
gaps during the start of AD in humans.161 As another targeting drug nanocarrier, Fe3O4-modified resveratrol
synthetic agent, the administration of essential fibro- liposomes demonstrated sustained and delayed drug
blast growth factor (bFGF) into the hippocampus may release. In vivo studies revealed that such nanoparticles
protect neuronal degeneration and improve learning could efficiently penetrate the BBB and enhance drug
impairments in AD rats. After intranasal treatment, concentration at the targeted area in the presence of an
Solanum tuberosum lectin coupled PEG-PLGA nano- external magnetic field.165 The in vitro and ex vivo nasal
particles may efficiently promote direct transport of mucosa penetration of resveratrol-loaded nanoemulsions
bFGF into the rat brain with decreased peripheral for PD was relatively high. The brain tissues of the
adverse reactions.162 group given resveratrol nanoemulsions had lower levels
Altogether, nanoformulations of synthetic drugs, like of degenerative alterations and oxidative stress indicators
erythropoietin, nicotinamide, rivastigmine, donepezil, via the antioxidant effect of resveratrol and fewer eosino-
memantine, estradiol, tarenflurbil, galantamine, clioquinol, philic lesions in the positive control group according to
and bFGF have shown different effects on AD through histopathological and biochemical tests.166 Resveratrol in
increasing neurogenesis, improving bioavailability, redu- polysorbate 80-coated poly(lactide) [PLA] nanoparticles
cing the aggregation of proteins and attenuating dysregu- can provide neuroprotection against behavioral and bio-
lated inflammation/apoptosis/oxidative stress. The pre- chemical properties. These findings suggested that resver-
clinical evidence on using nanoformulations of synthetic atrol-loaded PLA nanoparticles coated with polysorbate 80
drugs against AD is presented in Table 1. increased resveratrol concentration in the brain; thus, it
could be a promising nanomedical device and adjuvant
therapy for NDDs such as PD.167
Parkinson’s Disease and In the form of nanoformulation in a bind with poly-
Nanoformulations butyl cyanoacrylate, curcumin shows neuroprotective
Parkinson’s disease (PD) is a neurological disease effects in PD, crosses the BBB, and is thought to alleviate
caused by the progressive loss of dopaminergic neuro- PD symptoms.130 In another study, piperine and curcumin
nal cells in the substantia nigra (SN) pars compacta co-encapsulated glyceryl monooleate (GMO) nanoparti-
area of the basal ganglia. Oxidative stress, inflamma- cles increased suppression of S protein oligomerization
tion, and apoptosis are the main pathophysiological and fibril formation, decreased rotenone-induced toxicity,
characteristics of PD.130 It is thought that PD has a oxidative stress through reducing GSH depletion induced
significant hereditary connection, with mutations in the by rotenone, and apoptosis via reducing the ratio of Bcl-2
gene α-synuclein, which encodes for a protein that has to Bax, and initiation of the autophagic pathway in vitro.
been recognized as one of the contributing reasons for Furthermore, in vivo research showed that such nanopar-
the beginning of PD.20 ticles could cross the BBB, reverse rotenone-induced

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International Journal of Nanomedicine 2022:17
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Table 1 Nanoformulations of Phytochemicals and Synthetic Drugs in Combating AD and PD
Disease Component Nano Vehicle/Method Study Type Results References
AD Phytochemicals Nanoformulations
Resveratrol SLNs; ASDs In vitro: endothelial cells; In vivo: ↓formation of Aβ (1–42) aggregates, ↓quick clearance, ↓Aβ plaque density in the [126,184]
Aβ/APP/PS1 mouse cortex, caudoputamen, and hippocampus
NLCs In vitro: fresh nasal mucosa of ↑memory function, ↑permeation across nasal mucosa via decreasing the [127]
sheep; In vivo: male Sprague-Dawley crystallinity of particles through a lipid-oil mixture
rats
Curcumin PLGA; ASDs In vitro/ in vivo: Tg2576 mice ↑working and recall memory via activating canonical Wnt/β-catenin pathway, [129,184]
↑curcumin bioavailability, ↓rate of amyloid and plaque burden
PLGA In vitro: SK-N-SH cells, a human ↑curcumin stability [131]

neuroblastoma cell line
PLGA-PEG-B6 In vitro: HT22 cells ↑cellular absorption, ↑blood compatibility [134]
In vivo: APP/PS1 mice ↑spatial learning and memory performance [134]
Ex vivo ↓hippocampus-amyloid production and deposit, ↓tau hyperphosphorylation [134]
PLGA In vitro/in vivo: Wistar rats ↑NSC proliferation and neuronal differentiation in the hippocampus [133]
PLGA In vivo: Wistar rats ↑hippocampus neurogenesis, cognition, and memory, ↑canonical Wnt/β-catenin [133]
pathway
PLGA In vitro: rat hippocampal cells ↓Aβ aggregates [132]
Nanoliposomes In vitro: hAPPsw SH-SY5Y cell; In ↓Aβ-induced toxicity, ↓Aβ deposits [135]
vivo: APP/PS1 mice
Naringenin NEs In vitro: SH-SY5Y cells ↓APP, ↓BACE, ↓tau phosphorylation [136]
Quercetin PLGA; ASDs In vitro: SH-SY5Y cells; In vivo: Aβ/ Neurotoxicity of the Zn2+-Aβ42 system, ↑neuron cell survival by suppressing Zn2 [140,184]
+
C. elegan CL2006 -AB42 system, ↓aggregation of proteins
https://doi.org/10.2147/IJN.S347187
PLGA-NPs In vivo: APP/PS1 mice ↑cognitive functions and memory [140]
NPQ In vivo: SAMP8 mice ↑oral absorption, ↑bioavailability, ↑cognitive and memory [137]
DovePress
NPs In vivo: male Albino Wistar rats ↑residence period in the systemic circulation, ↑ bioavailability [139]
Cyclodextrin-dodecyl In vitro: SH-SY5Y cells ↓TLR4 and COX-2 signaling pathway, ↑BBB penetration, ↑bioavailability [138]
Fakhri et al
carbonate nanoparticles
313
(Continued)

314
Fakhri et al
Table 1 (Continued).
Disease Component Nano Vehicle/Method Study Type Results References

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Rosmarinic acid CRM197-ApoE-PAAM-CH- In vitro: SK-N-MC cells ↓degeneration of Aβ-insulted neurons, ↑BBB transportation, ↓caspase-3, and c-Jun [141]
PLGA
Epigallocatechin Nanolipidic In vitro: murine neuroblastoma ↑neuronal α-secretase, ↑oral bioavailability [142]
3-gallate cells; In vivo: male Sprague Dawley
rats
Nano In vitro: SH-SY-5Y cell ↓cellular toxicity, ↓Al3+-induced Aβ42 fibrillation, and neurotoxicity [143]
Stabilized selenium In vitro: PC12 cells ↓Aβ fibrillation, Aβ fibrils into harmless aggregates efficiently [144]
nanoparticles coated with
Tet-1 peptide
Ginsenoside PLGA In vitro: C6 rat glial cells and THP-1 ↑BBB permeability, ↓formation of Aβ plaques, and eventual neurodegeneration [150]
Rg3 human monocytic cells line
Ferulic acid SLN In vitro: human neuroblastoma cells ↓ROS compared cells [185]
(LAN 5)
Berberine MWCNTs In vitro: SH-SY5Y cells; In vivo: male ↑memory function recovery, ↑biochemical levels in brain tissue, and ↓Aβ [148]
Wistar rats
Sesamol SLN In vivo: male Wistar rats ↓neuronal malfunction, ↓ memory impairments by reducing oxidative stress [146]
Huperzine A Lf-TMC NPs In vitro/ex vivo: 16HBE and SH- ↑mucoadhesion, ↑widely dispersed in the brain over a long period [149]
SY5Y cell lines
Nanoformulations of synthetic drugs
Memantine PEG–PLGA In vitro/in vivo: APP/PS1 and C57BL/ ↓Aβ plaques [156]
6 mice
Donepezil Liposome In vivo: male Wistar rats ↑brain bioavailability [154]
Rivastigmine Liposome In vivo: male Wistar albino rats ↑memory recovery, ↓metabolic abnormalities [152]
SLN In vitro: Franz diffusion cell ↑diffusion and not affect nasociliary disruption or cell necrosis [153]
Tarenflurbil NPs/SLN In vitro: brain cells ↑brain biodistribution pattern, ↑ the pharmacokinetic behavior [160]
Estradiol PLGA In vivo: male Sprague–Dawley ↑brain estradiol levels [158]
Dovepress
Galantamine SLN In vitro/ in vivo: male New Zealand ↑substantial memory restoration potential, ↑bioavailability [155]
hydrobromide rabbits

Dovepress
bFGF STL-PEG-PLGA In vivo: male Sprague-Dawley rats ↓neuronal degeneration, ↓learning impairments, ↑direct transport of bFGF into [162]
the rat brain, ↓peripheral adverse reactions
PD Phytochemicals Nanoformulations
Resveratrol NPs In vitro/ in vivo: male albino Wistar ↑resveratrol blood levels for a more extended period, ↑bioavailability, ↑ [164]
rats pharmacological impact
Lips@Fe3O4 In vitro/ In vivo: male Sprague- ↑sustained and delayed drug release, ↑efficiently penetrate the BBB, ↑drug [165]
Dawley rats concentration at the targeted area in the presence of an external magnetic field
Vitamin E loaded resveratrol In vitro: brain cells ↓degenerative alterations, ↑antioxidant effect of resveratrol against hydrogen [166]
NEs peroxide
PS80-coated poly lactide NPs Ex vivo: C57BL/6 mice ↑resveratrol concentration in the brain [167]
Curcumin and GMO-NPs In vitro: rat PC12 cell line ↓αS protein oligomerization and fibril formation, ↓rotenone-induced toxicity, [168]
piperine ↓GSH depletion induced by rotenone, ↓ration of Bcl-2/Bax, ↑autophagic pathway
In vivo: male Balb/c mice and male ↑cross the BBB, ↓rotenone-induced motor coordination impairment, [168]
C57BL/6 mice ↓dopaminergic neuronal degeneration
Naringenin Vitamin E loaded NEs In vitro/in vivo: Wistar rats ↑muscular coordination, grip strength, ↑swimming activity, ↑naringenin in the [169]
brain, ↑ bioavailability, ↑GSH, ↑ SOD, ↓MDA
Gallic acid PEI-HAS-NPs In vitro: PC-12 cells ↓αSN aggregating, ↓hazardous oligomers. [186]
Nanoformulations of Synthetic Drugs
Levodopa NPs In vitro/ in vivo ↓dyskinesia [172]
Bromocriptine SLN based on a tristearin/ In vitro Controlled drug release by surrounding solid lipid barrier, firmly contained during [174]
tricaprin the extended time established
Chitosan In vivo: Swiss albino mice ↑absorption in the brain and protects catalepsy and akinesia [171]
Ropinirole PLGA In vitro/ in vivo: male Wistar rats ↓neurodegeneration [175]
PLN In vitro/in vivo: male albino mice ↓dose and dosing frequency, optimizing the therapeutic index, ↓side effects [177]
Selegiline NEs In vitro: neuro-2a neuroblastoma ↑GSH, ↑SOD, ↓TBARS ↑drug bioavailability, ↑brain uptake, ↓decreased dopamine [181]
DovePress
cell line depletion
NEs In vivo: Wistar rats ↓neurodamage caused by free radicals, ↓subsequent metabolic alterations [182]
Fakhri et al
(Continued)
315

motor coordination impairment, and prevent dopaminergic
Abbreviations: ↑, increase or upregulation; ↓, decrease or downregulation; ASDs, amorphous solid dispersions; αSN, α-synuclein; APP, amyloid precursor protein; BACE, β-secretase; BDNF, brain-derived neurotrophic factor; bFGF,
nanoparticles; NLCs, nanostructured lipid carriers; NP, nanoparticles; NPQ, nanoencapsulated quercetin; NSC, endogenous neural stem cells; PEI-HAS-NPs, polyethyleneimine-coated human serum albumin; PLGA-NPs, poly(lactide-co-
basic fibroblast growth factor; CAT, catalase; EGCG, epigallocatechin 3-gallate; MWCNTs, multiwalled carbon nanotubes; Lf-TMC NPs, lactoferrin-conjugated N-trimethylated chitosan nanoparticles; GMO, glyceryl monooleate; GSH,
glutathione; iNOS, intrinsic nitric oxide synthase; lips@Fe3O4, Fe3O4 modified liposomes; MDA, malondialdehyde; MSCs, mesenchymal stem cells; NEs, nano emulsions; PS80-coated poly lactide NPs, polysorbate 80 coated poly(lactide)
glycolide nanoparticles; PLGA-PEG-B6, poly(lactide-co-glycolide)-block-poly(ethylene glycol)) conjugated with B6 peptide; SLNs, solid lipid nanoparticles; ROS, reactive oxygen species; SOD, superoxide dismutase; STL-PEG-PLGA,
References
neuronal degeneration in a PD mouse model.168
Gaba et al found that combining vitamin E-loaded
[180]
[183]
[178]
naringenin (another flavonoid) nanoemulsion with conven-
tional medication (levodopa) effectively restored the con-
↓neuroinflammation, ↑dopaminergic neuronal function via blocking effect on glial-
Controlling motor deficits via its antioxidant potential, ↑SOD, ↑CAT, ↑ dopamine
↑oral bioavailability, ↓dose, and frequency of administration, effectively targeted sequences of 6-hydroxydopamine (6-OHDA), namely
improved muscular coordination, grip strength, and swim-
ming activity. It also increased the naringenin level in the
brain and boosted brain bioavailability in a rat model.
Although GSH and SOD levels were considerably greater,
malondialdehyde (MDA) showed a significant decrease in
the group treated with naringenin nanoemulsion intrana-
sally coupled with levodopa.169
Quercetin, a bioflavonoid present in a variety of fruits
and vegetable, has well-known neuroprotective through
apomorphine to the brain striatum
repairing mitochondrial electron transport chain abnorm-

alities and upregulated, increasing mitochondrial quality
control170 and anti-inflammatory properties. Furthermore,
derived S100B function
quercetin has a high capacity to remove ROS. Considering

its favorable benefits, low solubility and bioavailability
level in the brain
have limited its therapeutic uses; so, the bioavailability

and effectiveness of quercetin nanocrystals were higher
Results
in PD-like animals than in the naïve quercetin. There

was a substantial increase in antioxidant enzyme functions
and total GSH levels in the hippocampus region and a
In vivo: male Sprague-Dawley rats
In vivo: male Wistar albino rats
decrease in malondialdehyde levels.1

In vivo: male C57Bl/6 J mice
Therefore, the nanoformulations of resveratrol, curcu-

min, piperine, naringenin, quercetin, and gallic acid have
shown various therapeutic effects on PD by improving
bioavailability and reducing the harmful effects of rote-
Study Type
none. From the mechanistic point, nanophytochemicals

increase neurogenesis, suppress apoptotic pathways, and
Solanum tuberosum lectin coupled polyethylene glycol-polylactide-polyglycolide.
decrease oxidative stress/inflammation. Table 1 shows the

pre-clinical evidence on using nanoformulations of phyto-
Chitosan coated niosomes
Nano Vehicle/Method
chemicals against AD.
Parkinson’s Disease and Nanoformulation of

Synthetic Drugs
Chitosan
Several synthetic drugs are being indicated for PD symp-

SLNs
toms; however, the lack of efficacy urges the need to find a

way to counter their possible pharmacokinetic limitations.
Levodopa (a dopamine precursor) is the most therapeuti-
Apomorphine
Component
Pramipexole
Pentamidine
Table 1 (Continued).
cally beneficial medication in PD treatment. However, the

clinical response is unpredictable and inaccurate because
of its inconsistent oral absorption and variations in plasma
concentrations. Variations in motor function and the emer-
Disease
gence of drug-induced involuntary movements provide

difficulty in treating PD.171 In rats, levodopa

DovePress

administration can result in dyskinesia. Meanwhile, in Oral administration is a method of delivery that may be
dyskinetic rats, the treatment of levodopa methyl ester/ used in a variety of therapeutic conditions. Unfortunately,
benserazide-loaded nanoparticles decreased dyskinesia oral administration of apomorphine (a dopamine receptor
while avoiding the rise of molecules strongly linked with agonist) was ineffective due to fast degradation in the gastro-
the development of dyskinesia.172 intestinal tract and the first-pass effect, culminating in bioa-
Like another drug, bromocriptine is an ergot with vailability of 1.7%.179 Apomorphine oral bioavailability
dopamine receptor agonist activity that has been com- improved via utilizing SLNs as carriers. The drug’s dose
monly used in practice trials to postpone and reduce the and frequency of administration can be decreased. The in
destructive motor fluctuations coupled with prolonged vivo drug distribution data showed that SLNs effectively
levodopa treatment in PD. Bromocriptine protects dopa- focused apomorphine to the brain striatum, one of the most
minergic cells, directly and indirectly, to act as a dopamine damaged areas, substantially improving apomorphine’s capa-
receptor agonist.173 The promising results implied that city to treat PD.180 Compared to the free medication, selegi-
SLN based on a tristearin/tricaprin combination might be line (a monoamine oxidase inhibitor) encapsulated in
suggested as a novel method for administering bromocrip- nanoemulsions demonstrated greater antioxidant activity via
tine during PD treatment to provide controlled drug release increasing GSH and SOD while reducing the level of thio-
by the surrounding solid lipid barrier and firmly contained barbituric acid reactive substances (TBARS). Additionally,
during long time established. Furthermore, this method compared to a control group, a haloperidol-induced rat model
may offer a unique technique for achieving stable medica- of PD treated with the selegiline nanoemulsions exhibited
tion levels, enhancing patient adherence to therapy, and increased drug bioavailability and brain uptake, resulting in
decreasing long-term adverse effects.174 Also, intranasal decreased dopamine depletion.181 The findings suggested
treatment of bromocriptine-loaded chitosan nanoparticles that the proposed formulation might be a promising strategy
improved bromocriptine absorption in the brain and pro- for effective intranasal administration of selegiline into the
tected catalepsy and akinesia in a mouse model of PD.171 CNS, reducing neurodamage caused by free radicals and
A novel drug delivery system comprised PLGA nano- preventing subsequent metabolic alterations during PD.182
particles filled with ropinirole was created for PD treat- Pentamidine is among the most potent inhibitors of
ment. In the animal model tested, this approach could S100B activity, a crucial component in neuroinflammation
reverse PD-like symptoms.175 Ropinirole is a nonergoline that underpins the pathophysiology of PD, although its ability
dopamine receptor agonist that attaches to D2-receptors in to penetrate the BBB is restricted. To deal with this issue,
the striatum and substantia nigra with specificity similar to researchers utilized chitosan-coated niosomes with entrapped
dopamine. Its antiparkinsonian effect is elicited via pentamidine to restore dopaminergic neuronal function via
increasing striatal neuronal firing rates through the selec- its suppressing effect on glial-derived S100B function, which
tive activation of D2-dopamine receptors.176 The carrier resulted in a significant enhancement in parkinsonian motor
technology might provide an exciting way of CNS neu- dysfunctions.183 Overall, the nanoformulation of synthetic
rotherapeutic administration. Polymer-lipid hybrid nanodrugs such as levodopa, bromocriptine, ropinirole, selegiline,
particles might be regarded as a strong, safe, and stable apomorphine, pentamidine, and pramipexole have presented
alternative to traditional dose formulations, which would various protective roles on PD by reducing dyskinesia, les-
aid in reducing the dose and dosing frequency, optimizing sening the side effects of naive drugs, improving the bioa-
the therapeutic index, ensuring proper, eliminating peak- vailability of drugs, suppressing glial-function/oxidative
to-valley fluctuations, and lowering the risk of side stress, and enhancing dopamine level in the brain.
reactions.177 As another non-ergot-based dopamine ago- Table 1 shows the pre-clinical evidence on using nano-
nist, pramipexole is particularly useful when combined formulations of phytochemicals and synthetic drugs
with levodopa or monoamine oxidase-B inhibitors to against AD and PD.
slow the progression of PD. It has been revealed that
intranasal chitosan nanoparticles of pramipexole outper-
formed oral or solution dosage forms in controlling Amyotrophic Lateral Sclerosis and
motor deficits in a rotenone PD model via its antioxidant Nanoformulations
potential in increased SOD and CAT function while ALS, commonly known as motor neuron disease or Lou
enhanced dopamine level in the brain significantly.178 Gehrig’s disease, is a fast-progressing NDDs that causes

317
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muscular movement neurons to fail. ALS explicitly targets Verapamil cocktail liposomes reduced p-gp levels. TNF-α
motor neurons in the brain, brainstem, and spinal cord, or H2O2-induced increases in drug efflux transporters.
resulting in progressive motor neuron degeneration and Thus, a liposomal co-delivery method that may efficiently
muscular atrophy, leading to paralysis and death because transport riluzole to brain cells by decreasing efflux pumps
of respiratory failure. Gene mutations that affect regular with verapamil, a P-gp inhibitor, could circumvent riluzole
protein activity oxidative stress, protein misfolding and pharmacoresistance for enhancing ALS therapy.191 SLNs
aggregation, and mitochondrial malfunction neuroinflam- containing riluzole had higher drug loading and effective-
mation are implicated in the causes of ALS.22 ness than free riluzole and could transport more into the
brain with less indiscriminate biodistribution in rats.192
Amyotrophic Lateral Sclerosis and Phytochemicals
Besides, dimethyl fumarate is effective in the treatment
Nanoformulations
of recurrent ALS. On the other hand, such pills cause
In 2018, Ahmadi et al designed and conducted a rando-
flushing, gastrointestinal problems, and more significant
mized clinical trial to investigate the efficacy and safety of
side effects. As intranasal transport vehicles, simple tris-
oral capsules containing 80 mg nanomicelles curcuminoids
tearin SLN, coated with polysorbate 80 and cationized
combined with riluzole in patients with ALS. Results
with dimethyldioctadecylammonium chloride, were evalu-
emphasized that nanocurcumin was safe with no serious
ated. An in vitro investigation using a mouse brain micro-
adverse events, which increased the probability of survival
vascular endothelial cells model revealed that cationic
in treated patients, especially those with irritable bladder.23
SLN had greater brain penetration. The biodistribution of
According to some findings, pathological inclusions,
polysorbate 80-treated SLN in mice was investigated using
including SOD1 in ALS, are comparable to amyloid fibrils
fluorescence imaging following intraperitoneal or intrana-
produced in vitro. Fibrillar inclusions characterize the
sal administration. Thus, polysorbate 80-treated SLN
pathology of neural tissues in mouse models that express
entered the brain via intraperitoneal and intranasal routes;
human SOD1 mutations.187 Inhibiting SOD1 amyloid
however, they were primarily collected in the liver and
development could be a helpful approach for combating
spleen via the intraperitoneal way.193
ALS. Accordingly, curcumin prevented SOD1 fibrillation
Neurodegeneration in ALS mice is linked to the pro-
and promoted the formation of smaller, disordered aggre-
liferative repair efforts of ependymal stem progenitor cells,
gates. Curcumin nanoparticles with a more excellent water
typically dormant in the spinal cord. As a result, control-
solubility showed similar aggregation management as cur-
ling the development of ependymal stem progenitor cells
cumin bulk.188
might be a viable approach for preventing neurodegenera-
Furthermore, Tripodo et al introduced a new drug
tion. A mutant version of the human SOD1 gene is over-
delivery system to treat NDDs, especially ALS. A car-
expressed in the G93A-SOD1 transgenic mouse model of
ried-in-carrier system was produced via loading the curcu-
ALS. In addition, FM19G11, a hypoxia-inducible factor
min and mesenchymal stromal cells in the curcumin-
(HIF) modulator loaded in the gold nanoparticles, activates
loaded micelles. According to the research, these nanopar-
the PI3K/Akt and mitochondrial uncoupling protein
ticles achieved maximal loading in micelle-loaded
(UCP2) signal transduction pathways, which regulate
mesenchymal stromal cells in a matter of minutes, and
stemness, self-renewal, and proliferation is responsible
the loading was concentration-dependent. When naked
for this action. This research might pave the way for
curcumin was utilized, mesenchymal stromal cells showed
novel methods to slow the neurodegeneration and disease
apparent cytotoxicity; however, naive curcumin micelles
progression in ALS patients based on FM19G11-
shielded them from this impact.189
loaded.194
Amyotrophic Lateral Sclerosis and Nanoformulations Therefore, curcumin nanomicelle has protective effects
of Synthetic Drugs on ALS by regulating different dysregulated pathways like
The FDA has authorized only two drugs to manage ALS, SOD1 fibrillation. Additionally, nanomicelles improve the
riluzole and edaravone supporting neurons by removing bioavailability of curcumin and lower the cytotoxicity
ROS from the nervous system.190 Riluzole is one of only responses. Nanoformulations of synthetic drugs like rilu-
two approved drugs to treat ALS. Furthermore, because zole, edaravone, dimethyl fumarate, verapamil, and
riluzole is a P-glycoprotein (P-gp) substrate, its brain dis- FM19G11 improve their bioavailability and control the
tribution is hampered by efflux transporters at the BBB. development of ependymal stem progenitor cells by

DovePress

activating the PI3K/Akt and UCP2 signal transduction due to less neuronal loss.198 Following cerebral I/R, deli-
pathways. verable quercetin-loaded polymeric nanocapsules showed
increased brain uptake and impressive mitochondrial loca-
Stroke and Nanoformulation lization. In both young and old rats, this novel regulated
Cerebrovascular diseases are the primary cause of physical mitochondrial delivery of quercetin alleviated histopatho-
impairment, the second most significant cause of death, logical intensity by protecting mitochondrial structural and
and the main reason for hospital inpatient hospitalization functional integrity via sequestering ROS through increas-
for many patients. Stroke is the most frequent cerebrovas- ing GSH level and SOD and CAT activities regulating
cular illness and is the third-largest cause of mortality in mitochondrial ROS-driven apoptotic cell death.199
the developed world, causing 15 million injuries and 5 The primary active component of Panax notoginseng is
million fatalities each year. Ischemic stroke accounts for Panax notoginsenoside. When administered orally, the
80% of all stroke injuries caused by hypoperfusion, throm- unique Panax notoginsenoside-loaded core-shell hybrid
bosis, or embolism.29 Several variables, particularly oxi- liposomal vesicle (HLV) delivery method improved free
dative stress, apoptosis, edema caused by ionic imbalance, drug bioactivity. Furthermore, decreased brain water con-
and inflammation, are thought to have a role in the patho- tent and infarction volume detecting cerebral ischemia/
physiology of ischemic stroke.195 Clinical trials have reperfusion in the acute myocardial ischemia group com-
demonstrated that the biological activities of several herbal pared to the control group, lactate dehydrogenase (LDH)
formulations produced from natural products are related to in the serum, H2O2, and MDA increased significantly,
their antioxidant properties, which is considered as one of whereas SOD decreased significantly. Compared to the
the treatment mechanisms of ischemic stroke. The main model group, there were substantial restorations of the
issue with using phytochemicals in stroke treatment is enzymatic level in the Panax notoginsenoside-treated
their poor bioavailability, limiting their efficacy in clinical group, particularly in the Panax notoginsenoside-HLV-
studies.24 treated group the improved physicochemical
characteristics.200
Stroke and Phytochemicals Nanoformulations With stem cell treatment, the potential of overcoming
In rats with transient middle cerebral artery occlusion, the the damage caused by cerebral ischemia appeared promis-
intraarterial injection of resveratrol nanoparticles exhibited ing. The entrapped drug naringenin has a prolonged
additional safety from cerebral ischemia/reperfusion (I/R) release pattern in a nanoformulation of naringenin. The
damage. Resveratrol nanoparticles reduced oxidative stress findings suggest that naringenin-loaded gelatin-coated
caused by ischemia-reperfusion via decreasing MDA, polycaprolactone nanoparticles have protective effects on
avoided brain edema, rescued neurons from apoptosis human mesenchymal stem cells via reducing the inflam-
through decreasing Bax and cleaved caspase-3, and pro- matory responses (TNF-α, IL-1β, COX-2, and iNOS)
moted neurogenesis by increasing brain-derived neuro- through NF-κB pathways caused by oxygen-glucose
trophic factor (BDNF) expression.196 deprivation.201
Curcumin therapy has vascular protective benefits in As another phytochemical, retinoic acid nanoparticles
people at risk of stroke. Curcumin incorporated in a solid decreased microglial activation in N9 microglial cells;
lipid matrix of SLNs resists enzymatic breakdown during organotypic hippocampus slices culture and effectively
absorption and has a long circulation duration and lower inhibited LPS-induced release of nitric oxide (NO) and
elimination in vivo after absorption. After curcumin-SLNs the expression of iNOS and promoted arginase-1 and IL-
treatment, SOD, CAT, GSH, and mitochondrial complex 4 production.25
enzyme activity enhanced, but lipid peroxidation, nitrite, In summary, nanoformulations of resveratrol, curcu-
and acetylcholinesterase rates declined.197 In another min, quercetin, ginsenoside, naringenin, and retinoic acid
study, oral therapy with nanoencapsulated quercetin have various effects on stroke. Such therapeutic responses
could defend from oxidative damage by decreasing the are applied by reducing oxidative stress by enhancing the
expression of iNOS and caspase-3 activities and reducing activation of SOD, CAT, GSH, and mitochondrial complex
the loss of pyramidal neurons from the hippocampus CA1 enzymes. Nanophytochemicals also decrease Bax and
and CA3 subfields in young and old rats subjected to I/R. cleaved caspase-3, increase BDNF expression, and reduce
Early therapy with nanodrugs improves survival chances the loss of pyramidal neurons from the hippocampus CA1

319
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and CA3. Nanophytocompounds also reduce the inflam- angiogenesis in the ischemic area by releasing VEGF and
matory mediators (eg, TNF-α, IL-1β, COX-2, and iNOS) Ang1, providing a favorable niche for neural repair in the
through NF-κB pathways, inhibiting LPS-induced nitric later stages of stroke. In addition, such nanoformulation
oxide (NO) promoted arginase-1 and IL-4 production. stimulated vascularization and axonal development.207
After brain ischemia, Zhao et al utilized a transferrin-coupled
Stroke and Nanoformulations of Synthetic Drugs liposomes vector to supply VEGF to rats. They discovered
The findings revealed that recombinant tissue plasminogen that a single intravenous injection of the vector induced
activator (rtPA) to PEG-PCL nanoparticles equal 10% of a brain-specific VEGF production, improved neuroprotection,
normal rtPA dosage in dissolving fibrin clots. Such nano- and stimulated neovascularization.208
particles had a neuroprotective effect after localized cere- In all, the nanoformulations of rtPA, fasudil, VEGF,
bral ischemia, as seen by reduced infarct volume and Ang-1, and VEGF modulate stroke symptoms by reducing
improved neurological impairment. Such conjugation infarct volume and neurological impairment, increasing
showed a half-life of about 18 times greater than free angiogenesis in the ischemic area, elevating vasculariza-
rtPA.202 Medication with liposomal fasudil before tPA tion and axonal development and increasing neuroprotec-
may reduce the chance of tPA-derived cerebral hemor- tion via reducing cerebral infarcts/neovascularization.
rhage and lengthen the therapeutic time window of throm- Table 2 shows the pre-clinical evidence on the use of
bolytic therapy. The combined treatment may be a helpful phytochemical/synthetic nanoparticles against ALS and
therapeutic alternative for ischemic stroke.203 The antiox- stroke.
idant capabilities of CeO nanoparticles aided cell viability
and dramatically decreased free radical generation. CeO Other NDDs and Nanoformulation
nanoparticles substantially reduced cell death in an animal Nanoformulations have also shown potential to combat
model of stroke. Besides, Pt nanoparticles have been used other NDDs, including HD and MS. HD is a neurological
as ROS scavengers in vitro and in vivo in mice, reducing condition that is inherited in an autosomal dominant man-
the oxidative stress caused by ischemia. Similarly, Pt ner. HD begins in middle age and progresses to death 15–20
nanoparticles enhanced motor function and reduced infarct years later, with the following signs and symptoms, includ-
volume in the brain.26 ing uncontrollable movement problems, cognitive deficits,
Single-walled carbon nanotubes showed an anti- and mental aspects. This disease is defined by an irregular
inflammatory impact in a rat stroke model and prevented repeat of the Huntingtin gene’s triplet cytosine-adenine-
neurons from ischemia injury.204 Local administration of guanine (CAG), which is translated at the protein level by
SOD-loaded nanoparticles produced persistent protective a polyglutamine increase at the NH2-terminus of the protein
implications resulting in a 65% decrease in infarct volume, huntingtin (HTT).209 The precise etiology of neuronal death
whereas SOD solution therapy increased infarct volume by in HD is unknown. However, the main drivers are glutamate
25%. The prolonged lifespan of rats treated with nanopar- excitotoxicity, mitochondrial malfunction, poor protein
ticles indicated the superior protective impact of SOD- degradation, protein misfolding, caspase activation, tran-
loaded nanoparticles. An angiogenic growth factor, vascu- scriptional pathway dysregulation, decreased proteasome
lar endothelial growth factor (VEGF), stimulated neuro- activity, and proteolysis abnormalities.210
genesis and cerebral angiogenesis, which reduced Curcumin SLNs were administered to rats treated with
ischemic brain damage. VEGF-encoding plasmids were 3-nitropropionic-acid (3-NP). This toxin induces HD-like
encased in liposomes functionalized with transferrin for neuropathology in rodents, leading to a decline in HD-like
intravenous administration, allowing them to cross the neurodegeneration and a considerable increase in mito-
BBB.29 chondrial complex function and cytochrome rates. The
In another study, VEGF and angiopoietin-1 (Ang1) are results demonstrated that the enhanced bioavailability of
two essential factors triggering angiogenesis.205 Despite curcumin by SLN encapsulation has a distinct advantage
VEGF and Ang1’s potential therapeutic potential, their in over curcumin alone. Curcumin-SLNs indeed recovered
vivo short half-life through direct delivery made some GSH levels and SOD activity. Compared to 3-NP-treated
limitations.206 Additional studies suggested that the hyaluro- rats, curcumin-SLN-treated rats demonstrated a significant
nic acid-based biodegradable hydrogel scaffold, mixed with difference in neuromotor coordination.211 In a recent
PLGA hydrogel, is a potential material capable of inducing report, curcumin-loaded nanoparticles based on

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Table 2 Phytochemical/Synthetic Nanoformulations Against ALS and Stroke
Disease Component Nano Vehicle/ Study Types Results References
Method
ALS Phytochemicals Nanoformulations
Curcumin NPs In vitro: MSCs Without cytotoxicity [189]
NPs In vitro: human monocytic THP-1 cell ↓SOD1, ↑water solubility [188]
Nanomicelles Clinical trial ↑safety, ↓serious adverse effects [23]
Nanoformulations of Synthetics Drugs
FM19G11 Gold In vitro: epSPCs ↑self-renewal, ↑PI3K/Akt and UCP2 and proliferation of epSPCs [194]
Riluzole Liposome In vitro: mouse brain endothelial bEND.3 and ↑uptake of riluzole in BBB cell model, ↑ TNF-α or H2O2 [191]
astrocyte C8D1A cells
Stroke Phytochemicals Nanoformulations
Resveratrol NPs In vivo: male Sprague-Dawley rats ↓oxidative stress, ↓MDA, ↓brain edema, ↓apoptosis, ↓Bax and caspase-3, ↑neurogenesis, ↑BDNF expression. [196]
Curcumin SLNs In vivo: male Wistar rats ↑circulation duration, ↑SOD, ↑CAT, ↑GSH, ↑mitochondrial complex enzyme activity, ↓lipid peroxidation, ↓nitrite, ↓ [197]
acetylcholinesterase
Quercetin Nanoencapsulated In vivo: male Sprague Dawley rats ↓iNOS, ↓caspase-3, ↓loss of pyramidal neurons [198]
Polymeric nanocapsules In vivo: male Wistar rats ↑brain uptake, impressive mitochondrial localization, protecting mitochondrial structural and functional integrity [199]
via sequestering ROS, ↑GSH level, SOD and CAT activities
Panax notoginsenoside HLV In vivo: male Sprague Dawley rats ↑bioactivity, ↓brain water content, ↓infarction volume, ↑ SOD, ↓LDH, H2O2, MDA [200]
Naringenin Gel-c-PCL In vitro: MSCs ↑release pattern, ↓TNF-α, IL-1β, COX2 and iNOS) via ↓NF-κB [201]
Retinoic Acid NPs In vitro: Murine N9 microglia; Organotypic ↓microglia activation, ↓NO and the expression of iNOS, promoted arginase-1 and IL-4 [25]
hippocampal slices culture
Nanoformulations of Synthetic Drugs

rtPA PEG-PCL In vivo: Sprague Dawley rats ↓infarct volume, ↓neurological impairment, ↑half-life that is about 18 time greater than free rtPA [202]
Fasudil Liposomal In vivo: male Sprague-Dawley rats ↓tPA-derived cerebral hemorrhage, ↑TTW of thrombolytic therapy with tPA [203]
VEGF and Ang-1 HA–PLGA In vitro: HUAECs/primary NSCs; in vivo: ↑angiogenesis in the ischemic area, ↑ vascularization and axonal development. [207]
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C57BL/6J rats
VEGF Tf-PLs In vivo: male Sprague-Dawley rats ↑brain-specific VEGF production, ↑neuroprotection via reducing cerebral infarcts, ↑neovascularization [208]
Fakhri et al
Abbreviations: ↑, increase or upregulation; ↓, decrease or downregulation; Akt, protein kinase B; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; CAT, catalase; COX2, cyclooxygenase-2; GSH,
glutathione; H2O2, hydrogen peroxide; HA–PLGA, hyaluronic acid poly(lactic-co-glycolic acid); HLV, hybrid liposomal vesicle; gel-c-PCL NPs, gelatin-coated polycaprolactone nanoparticles; IL-1β, Interleukin; iNOS, nitric oxide synthase;
321
INVITE MC, curcumin loaded micelles; LDH, lactate dehydrogenase; MDA, Malondialdehyde; MSCs, mesenchymal stem cells; NEs, nano emulsions; PS80-coated poly lactide NPs, polysorbate 80 coated poly(lactide) nanoparticles; NF-kβ,
nuclear factor-kβ; NLCs, nanostructured lipid carriers; NO, nitric oxide; NP, nanoparticles; NSC, endogenous neural stem cells; PI3K, phosphatidylinositol 3-kinase; SLNs, solid lipid nanoparticles; ROS, reactive oxygen species; SOD,
superoxide dismutase; Tf-PLs, transferrin-coupled liposomes; TNF-α, Tumor necrosis factor; tPA, tissue-type plasminogen activator; VEGF, vascular endothelial growth factor; UCP2, mitochondrial uncoupling protein.

amphiphilic hyaluronan-conjugate showed neuroprotective enhanced remyelination after damage. Moreover, serum
properties, in an in vitro model of HD.212 exosomes nasally given to naive rats enhanced myelin
In another study, treatment with rosmarinic acid-loaded content, oligodendrocyte precursor cell, and neural stem
SLNs significantly reduces impairments in body weight, cell levels and reduced oxidative damage in hippocampal
beam walk, locomotor and motor coordination, as well as slice cultures. PLGA nanoparticles covalently cross-
3-NP-induced striatal oxidative stress via restored endo- linked to myelin peptides reduced inflammation and
genous antioxidants enzyme (CAT and GSH). The impor- modulated effector T cell function. CeO nanoparticles
tance of choosing the nasal route over the i.v. route is became stable with citrate/EDTA and acted as an antiox-
demonstrated by the optimal brain medication idant in CNS ROS levels in C57/Bl6 MOG EAE mice
concentration.213 after IV treatment. This therapy reduced clinical symp-
MS is a chronic immune-mediated demyelinating con- toms and motor deficits while reducing CNS damage
dition of the CNS that can be relapsing-remitting or pro- caused by free radical buildup.214 In another study, arti-
gressive, with axon loss and paralysis as a result. MS ficial neurotrophins are highlighted as promising agents
generally develops in adults between the ages of 20 and against neurodegeneration.218 The potential uses of phy-
50, and women are more prone to developing MS. MS is tochemical/synthetic nanoformulations against multiple
characterized by a wide range of persistent physical, neu- NDDs are provided in Figure 3.
rological, and psychotic disorders, including muscular So, nanoformulations of phytochemicals and synthetic
weakness, weak reflexes, muscle spasms, trouble moving, drugs critically modulated dysregulated mediators in
poor coordination, and imbalance. Nanotechnology is a NDDs, thereby combat neurodegeneration.
promising method that has made significant contributions Table 3 shows the pre-clinical evidence on the use of
to diagnosing and treating CNS-related diseases like phytochemical/synthetic nanoparticles against HD
MS.214 Like another drug, dimethyl fumarate is a potential and MS.
medication for treating MS; however, it is linked with
repeated dosage, inadequate brain penetration, and gastro-
intestinal flushing. Studies demonstrated the superiority of Conclusion and Future Outlook
nanocarriers carrying dimethyl fumarate in a once-daily NDDs are defined as the progressive loss of neuronal
dosing regimen vs thrice-daily plain dimethyl fumarate architecture or activity, which is usually followed by neu-
administration on critical metrics such as motor coordina- ronal death. The most prevalent neurodegenerative condi-
tion, grip strength, weight, and locomotor activity.215 The tions are AD, PD, ALS, stroke, HD, and MS. Several
same study showed that SLN-dimethyl fumarate improves dysregulated pathways are involved in the pathogenesis
bioavailability, biological residence, and brain absorption, of NDDs, including neuronal oxidative stress, neuroapop-
implying that lipid nanocarrier formulations might help tosis, and neuroinflammation (Figure 4). Such complex
treat MS adequately.216 Also, an in vitro investigation of pathophysiological mechanisms and the pharmacokinetics
fluorescent SLN penetration using a mouse brain micro- limitations, lower efficacy, and higher side effects of con-
vascular endothelial cell model revealed that cationic SLN ventional therapies urge the need to investigate alternative
had greater permeability values than SLN treated with formulations and novel treatments. In recent decades, phy-
polysorbate 80. The in vivo images showed that polysor- tochemicals have been highlighted as a hopeful therapeutic
bate 80-treated SLN could reach the brain, although they agent in the prevention and treatment of cancer. Despite
mostly collected in the liver and spleen.217 the effectiveness of plant secondary metabolites, they
For example, exosomes, or tiny nanovesicles formed often suffer from poor bioavailability, low solubility,
by dendritic cells, contain proteins and RNAs that help instability, decreased absorption, and low selectivity,
repair myelin sheaths. Exosomes have been proposed as a which limit their therapeutic applications in cancer.
replacement for liposomes in administering medicinal Besides, rapid metabolism, chemical degradation, and
drugs. Exosomes do not have toxicity effects and can clearance of phytochemicals make their low plasma con-
quickly cross the BBB, giving them great therapeutic centration in clinical trials. The application of polymeric/
benefits. By encouraging preoligodendrocytes to differ- metallic nanoparticles, micelle, liposome, and solid-lipid
entiate into myelin-producing cells, dendritic-derived nanoparticles has favorably overcome these pharmacoki-
exosomes significantly increased myelination and netic limitations through enhancing cellular uptake,

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Figure 3 The potential uses of phytochemical/synthetic nanoformulations against multiple neurodegenerative diseases.
Abbreviations: AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; bFGF, fibroblast growth factor; EPO, erythropoietin; DMF, dimethyl fumarate; EGCG,
epigallocatechin 3-gallate; GA, Gallic acid; NPs, nanoparticles; PD, Parkinson’s disease; RA, rosmarinic acid; rtPA, recombinant tissue plasminogen activator.
bioavailability, efficacy and specificity of anticancer sec- multi-target phytochemicals used against NDDs have
ondary metabolites.6,219 shown a bright future against AD, PD, ALS, stroke, HD,
Therefore, nanoparticles have shown a new gate to and MS. In this line, liposomes, metal, semiconductor,
pave the road in combating NDDs through their intrinsic polymeric nanoparticles, SLN, NLC, and NEs, have all
neuroprotective effects, restricting pharmacokinetic limita- demonstrated their ability to improve brain transportation
tions, improving biodegradability/biocompatibility, and by more readily passing into the CNS.
easily passing BBB. In recent decades, novel delivery The current manuscript highlights novel delivery
systems of conventional drugs and the application of systems of phytochemicals and synthetic drugs against
Table 3 Phytochemical/Synthetic Nanoformulations in Combating HD and MS

Disease Component Nano Study Types Results References
Vehicle/
Method
HD Phytochemicals Nanoformulations
Curcumin SLN In vivo: female Wistar Rats ↑bioavailability, ↑GSH, ↑SOD [211]
Rosmarinic SLN In vitro/in vivo: Wistar rat ↓3-NP-induced impairments, ↓oxidative stress [213]
acid through ↑GSH and CAT, ↑brain medication
concentration
MS Nanoformulations of Synthetics Drugs
Dimethyl Nanocarriers In vivo: Laca mice ↓dosage frequency [215]

fumarate
SLN In vitro: SH-SY5Y cells; In vivo: ↑bioavailability, ↑biological residence, ↑brain [216]
Wistar rats absorption
SLN In vitro: mouse brain microvascular ↑permeability values and brain absorption [217]
endothelial cells; In vivo: Male,
athymic mice
Abbreviations: ↑, increase or upregulation; ↓, decrease or downregulation; 3-NP, 3-nitropropionic-acid; CAT, catalase; GSH, glutathione; HD, Huntington’s disease; MS,
multiple sclerosis; NP, nanoparticles; SLNs, solid lipid nanoparticles; SOD, superoxide dismutase.

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Figure 4 Nanophytochemicals and nanosynthetic drugs pave the road in combating neurodegenerative diseases, targeting different dysregulated mechanisms.
Abbreviations: AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; NEs, nanoemulsions; NPs, nanoparticles; PD, Parkinson’s disease; PEG, polyethylene glycol;
SLNs, solid lipid nanoparticles.
NDDs. Such studies may reshape the therapeutic strate- ● Nano delivery systems drawback the pharmacokinetic
gies in the prevention/treatment of NDDs, towards novel limitation of phytochemicals and synthetic drugs and
delivery systems of plant-derived secondary metabolites augment the efficacy of neuroprotective agents
and synthetic drugs that target central dysregulated ● The nanoformulations of phytochemicals and synthetic
mechanisms possessing higher efficacy and a lower drugs critically modulate multiple dysregulated path-
rate of side effects/drug resistance. Although there are ways in NDDs
yet some concerns on the neurotoxicity of novel deliv- ● The neurotoxicity of some novel delivery systems
ery systems, which requested additional studies.220 requests for additional pre-clinical studies
Further pre-clinical studies are needed to elucidate the
precise tools and evaluate additional suitable novel sys- Acknowledgments
tems (eg, peptide engineering techniques, DNA nano- This research did not receive any specific grant from
cages, nanoenzymes) against cancer chemoresistance. funding agencies in the public, commercial, or not-for-
Besides, alternative therapies against NDDs and well- profit sectors.
controlled clinical trials for possible applicability and
neurotoxicity of delivery systems are critical steps in Author Contributions
combating cancer. All authors made a significant contribution to the work
reported, whether that is in the conception, study
Highlights design, execution, acquisition of data, analysis and
● Oxidative stress, inflammation, apoptosis, and protein interpretation, or in all these areas; took part in draft-
aggregation are critical dysregulated pathways in neu- ing, revising or critically reviewing the article; gave
rodegenerative diseases (NDDs) final approval of the version to be published; have
● Some nanoformulations have shown neuroprotective agreed on the journal to which the article has been
effects through anti-protein aggregation, antioxidant, submitted; and agree to be accountable for all aspects
anti-inflammatory, and antiapoptotic roles of the work.

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Disclosure 18. Re F, Gregori M, Masserini M. Nanotechnology for neurodegen-

erative disorders. Maturitas. 2012;73(1):45–51. doi:10.1016/j.
The authors report no conflicts of interest in this work. maturitas.2011.12.015
19. Wilson B, Geetha KM. Neurotherapeutic applications of nanome-
dicine for treating Alzheimer’s disease. J Control Release.
References 2020;325:25–37. doi:10.1016/j.jconrel.2020.05.044
20. Sim TM, Tarini D, Dheen ST, Bay BH, Srinivasan DK.
1. Moradi SZ, Momtaz S, Bayrami Z, Farzaei MH, Abdollahi M. Nanoparticle-based technology approaches to the management
Nanoformulations of herbal extracts in treatment of neurodegen- of neurological disorders. Int J Mol Sci. 2020;21(17):6070.
erative disorders. Front Bioeng Biotechnol. 2020;8:238. doi:10.3390/ijms21176070
doi:10.3389/fbioe.2020.00238 21. Babazadeh A, Vahed FM, Jafari SM. Nanocarrier-mediated brain
2. Kumar H, Bhardwaj K, Nepovimova E, et al. Antioxidant func- delivery of bioactives for treatment/prevention of neurodegenera-
tionalized nanoparticles: a combat against oxidative stress. tive diseases. J Control Release. 2020;321:211–221. doi:10.1016/
Nanomaterials. 2020;10(7):1334. doi:10.3390/nano10071334 j.jconrel.2020.02.015
3. Gupta J, Fatima MT, Islam Z, Khan RH, Uversky VN, Salahuddin 22. Wang G, Rayner S, Chung R, Shi B, Liang X. Advances in
P. Nanoparticle formulations in the diagnosis and therapy of nanotechnology-based strategies for the treatments of amyo-
Alzheimer’s disease. Int J Biol Macromol. 2019;130:515–526. trophic lateral sclerosis. Mater Today Bio. 2020;6:100055.
doi:10.1016/j.ijbiomac.2019.02.156 doi:10.1016/j.mtbio.2020.100055
4. Mechan A, Yuan J, Hatzidimitriou G, Irvine RJ, McCann UD, 23. Ahmadi M, Agah E, Nafissi S, et al. Safety and efficacy of nano-
Ricaurte GA. Pharmacokinetic profile of single and repeated oral curcumin as add-on therapy to riluzole in patients with amyotrophic
doses of MDMA in squirrel monkeys: relationship to lasting
lateral sclerosis: a pilot randomized clinical trial. Neurotherapeutics.
effects on brain serotonin neurons. Neuropsychopharmacology.
2018;15(2):430–438. doi:10.1007/s13311-018-0606-7
2006;31(2):339–350. doi:10.1038/sj.npp.1300808
24. Mutoh T, Mutoh T, Taki Y, Ishikawa T. Therapeutic potential of
5. Agarwal H, Nakara A, Shanmugam VK. Anti-inflammatory
natural product-based oral nanomedicines for stroke prevention. J
mechanism of various metal and metal oxide nanoparticles synthe-
Med Food. 2016;19(6):521–527. doi:10.1089/jmf.2015.3644
sized using plant extracts: a review. Biomed Pharmacother.
25. Bernardo-Castro S, Albino I, Barrera-Sandoval ÁM, et al.
2019;109:2561–2572. doi:10.1016/j.biopha.2018.11.116
Therapeutic nanoparticles for the different phases of ischemic
6. Fakhri S, Moradi SZ, Farzaei MH, Bishayee A. Modulation of
stroke. Life. 2021;11(6):482. doi:10.3390/life11060482
Dysregulated Cancer Metabolism by Plant Secondary
26. Sarmah D, Saraf J, Kaur H, et al. Stroke management: an emer-
Metabolites: A Mechanistic Review. Elsevier; 2020.
ging role of nanotechnology. Micromachines. 2017;8(9):262.
7. Ma -D-D, Yang W-X. Engineered nanoparticles induce cell apop-
27. Zeng Y, Li Z, Zhu H, Gu Z, Zhang H, Luo K. Recent advances in
tosis: potential for cancer therapy. Oncotarget. 2016;7(26):40882.
nanomedicines for multiple sclerosis therapy. ACS Appl Bio
doi:10.18632/oncotarget.8553
Mater. 2020;3(10):6571–6597. doi:10.1021/acsabm.0c00953
8. Ross C, Taylor M, Fullwood N, Allsop D. Liposome delivery
28. Mukherjee S, Madamsetty VS, Bhattacharya D, Roy Chowdhury
systems for the treatment of Alzheimer’s disease. Int J
S, Paul MK, Mukherjee A. Recent advancements of nanomedi-
Nanomedicine. 2018;13:8507. doi:10.2147/IJN.S183117
cine in neurodegenerative disorders theranostics. Adv Funct
9. Moghaddam RH, Samimi Z, Moradi SZ, Little PJ, Xu S, Farzaei
MH. Naringenin and naringin in cardiovascular disease preven- Mater. 2020;30(35):2003054. doi:10.1002/adfm.202003054
tion: a preclinical review. Eur J Pharmacol. 2020;887:173535. 29. Gao H, Pang Z, Jiang X. Targeted delivery of nano-therapeutics
doi:10.1016/j.ejphar.2020.173535 for major disorders of the central nervous system. Pharm Res.
10. Fakhri S, Pesce M, Patruno A, et al. Attenuation of Nrf2/Keap1/ 2013;30(10):2485–2498. doi:10.1007/s11095-013-1122-4
ARE in Alzheimer’s disease by plant secondary metabolites: a 30. Asil SM, Ahlawat J, Barroso GG, Narayan M. Nanomaterial based
mechanistic review. Molecules. 2020;25(21):4926. doi:10.3390/ drug delivery systems for the treatment of neurodegenerative diseases.
molecules25214926 Biomater Sci. 2020;8(15):4109–4128. doi:10.1039/D0BM00809E
11. Moradi SZ, Jalili F, Farhadian N, et al. Polyphenols and neuro- 31. Calzoni E, Cesaretti A, Polchi A, Di Michele A, Tancini B,
degenerative diseases: focus on neuronal regeneration. Crit Rev Emiliani C. Biocompatible polymer nanoparticles for drug deliv-
Food Sci Nutr. 2020:1–16. doi:10.1080/10408398.2020.1865870 ery applications in cancer and neurodegenerative disorder thera-
12. Milatovic D, Zaja-Milatovic S, Breyer RM, Aschner M, Montine pies. J Funct Biomater. 2019;10(1):4. doi:10.3390/jfb10010004
TJ. Neuroinflammation and oxidative injury in developmental 32. An HW, Mamuti M, Wang X, et al. Rationally Designed Modular
neurotoxicity. In: Reproductive and Developmental Toxicology. Drug Delivery Platform Based on Intracellular Peptide Self-
Elsevier; 2017:1051–1061. assembly. Wiley Online Library; 2021:20210153.
13. DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil 33. Zhang R, Yan X, Fan K. The advances of nanozyme in brain
is in the details. J Neurochem. 2016;139:136–153. doi:10.1111/ disease. In: Nanomedicine in Brain Diseases; 2019:139–179.
jnc.13607 34. Fakhri S, Piri S, Moradi SZ, Khan H. Phytochemicals targeting
14. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. oxidative stress, interconnected neuroinflammatory and neuroa-
Neuronal cell death. Physiol Rev. 2018;98(2):813–880. poptotic pathways following radiation. Curr Neuropharmacol.
doi:10.1152/physrev.00011.2017 2021;19. doi:10.2174/1570159X19666210809103346
15. Abbaszadeh F, Fakhri S, Khan H. Targeting apoptosis and autop- 35. Tee JK, Ong CN, Bay BH, Ho HK, Leong DT. Oxidative stress
hagy following spinal cord injury: therapeutic approaches to by inorganic nanoparticles. WIREs Nanomed Nanobiotechnol.
polyphenols and candidate phytochemicals. Pharmacol Res. 2016;8(3):414–438. doi:10.1002/wnan.1374
2020;160:105069. doi:10.1016/j.phrs.2020.105069 36. Manke A, Wang L, Rojanasakul Y. Mechanisms of nanoparticle-
16. Ayaz M, Sadiq A, Junaid M, Ullah F, Subhan F, Ahmed J. induced oxidative stress and toxicity. Biomed Res Int.
Neuroprotective and anti-aging potentials of essential oils from 2013;2013:1–15. doi:10.1155/2013/942916
aromatic and medicinal plants. Front Aging Neurosci. 2017;9:168. 37. Eriksson P, Tal AA, Skallberg A, et al. Cerium oxide nanoparti-
17. Nowacek A, Kosloski LM, Gendelman HE. Neurodegenerative cles with antioxidant capabilities and gadolinium integration for
disorders and nanoformulated drug development. Nanomedicine. MRI contrast enhancement. Sci Rep. 2018;8(1):6999. doi:10.
2009;4(5):541–555. doi:10.2217/nnm.09.37 1038/s41598-018-25390-z

325
DovePress

38. Caputo F, De Nicola M, Sienkiewicz A, et al. Cerium oxide 55. Kim M-H, Seo J-H, Kim H-M, Jeong H-J. Aluminum-doped zinc
nanoparticles, combining antioxidant and UV shielding proper- oxide nanoparticles attenuate the TSLP levels via suppressing
ties, prevent UV-induced cell damage and mutagenesis. caspase-1 in activated mast cells. J Biomater Appl. 2016;30
Nanoscale. 2015;7(38):15643–15656. doi:10.1039/C5NR03767K (9):1407–1416. doi:10.1177/0885328216629822
39. Ragg R, Schilmann AM, Korschelt K, et al. Intrinsic superoxide 56. Sumbayev VV, Yasinska IM, Garcia CP, et al. Gold nanoparticles
dismutase activity of MnO nanoparticles enhances the magnetic downregulate interleukin-1β-induced pro-inflammatory responses.
resonance imaging contrast. J Mater Chem B. 2016;4(46):7423– Small. 2013;9(3):472–477. doi:10.1002/smll.201201528
7428. doi:10.1039/C6TB02078J 57. de Carvalho TG, Garcia VB, de Araújo AA, et al. Spherical
40. Niu J, Azfer A, Rogers LM, Wang X, Kolattukudy PE. neutral gold nanoparticles improve anti-inflammatory response,
Cardioprotective effects of cerium oxide nanoparticles in a trans- oxidative stress and fibrosis in alcohol-methamphetamine-induced
genic murine model of cardiomyopathy. Cardiovasc Res. 2007;73 liver injury in rats. Int J Pharm. 2018;548(1):1–14. doi:10.1016/j.
(3):549–559. doi:10.1016/j.cardiores.2006.11.031 ijpharm.2018.06.008
41. Yun X, Maximov VD, Yu J, Vertegel AA, Kindy MS. 58. Shaikh S, Nazam N, Danish Rizvi SM, Hussain T, Farhana A,
Nanoparticles for targeted delivery of antioxidant enzymes to Choi I. Anti-amyloid aggregating gold nanoparticles: can they
the brain after cerebral ischemia and reperfusion injury. J Cereb really be translated from bench to bedside for Alzheimer’s disease
Blood Flow Metab. 2013;33(4):583–592. doi:10.1038/ treatment? Curr Protein Pept Sci. 2020;21(12):1184–1192.
jcbfm.2012.209 doi:10.2174/1389203721666200226101930
42. Xu Y, Liu H, Song L. Novel drug delivery systems targeting 59. Yang T, Yao Q, Cao F, Liu Q, Liu B, Wang X-H. Silver nano-
oxidative stress in chronic obstructive pulmonary disease: a particles inhibit the function of hypoxia-inducible factor-1 and
review. J Nanobiotechnology. 2020;18(1):145. doi:10.1186/ target genes: insight into the cytotoxicity and antiangiogenesis.
s12951-020-00703-5 Int J Nanomedicine. 2016;11:6679. doi:10.2147/IJN.S109695
43. Gil D, Rodriguez J, Ward B, Vertegel A, Ivanov V, Reukov V. 60. Sheikpranbabu S, Kalishwaralal K, Venkataraman D, Eom SH,
Antioxidant activity of SOD and catalase conjugated with nano- Park J, Gurunathan S. Silver nanoparticles inhibit VEGF-and IL-
crystalline ceria. Bioengineering. 2017;4(1):18. doi:10.3390/ 1β-induced vascular permeability via Src dependent pathway in
bioengineering4010018 porcine retinal endothelial cells. J Nanobiotechnology. 2009;7
44. Reddy MK, Labhasetwar V. Nanoparticle-mediated delivery of (1):1–12. doi:10.1186/1477-3155-7-8
superoxide dismutase to the brain: an effective strategy to reduce 61. Jang S, Park JW, Cha HR, et al. Silver nanoparticles modify
ischemia-reperfusion injury. FASEB J. 2009;23(5):1384–1395. VEGF signaling pathway and mucus hypersecretion in allergic
doi:10.1096/fj.08-116947 airway inflammation. Int J Nanomedicine. 2012;7:1329.
45. Reddy MK, Wu L, Kou W, Ghorpade A, Labhasetwar V. doi:10.2147/IJN.S27159
Superoxide dismutase-loaded PLGA nanoparticles protect cul- 62. Franková J, Pivodová V, Vágnerová H, Juráňová J, Ulrichová J.
tured human neurons under oxidative stress. Appl Biochem Effects of silver nanoparticles on primary cell cultures of fibro-
Biotechnol. 2008;151(2):565. doi:10.1007/s12010-008-8232-1 blasts and keratinocytes in a wound-healing model. J Appl
46. Castellani S, Trapani A, Spagnoletta A, et al. Nanoparticle deliv- Biomater Funct Mater. 2016;14(2):137–142. doi:10.5301/
ery of grape seed-derived proanthocyanidins to airway epithelial jabfm.5000268
cells dampens oxidative stress and inflammation. J Transl Med. 63. Zhu C, Zhang S, Song C, et al. Selenium nanoparticles decorated
2018;16(1):140. doi:10.1186/s12967-018-1509-4 with Ulva lactuca polysaccharide potentially attenuate colitis by
47. Kajita M, Hikosaka K, Iitsuka M, Kanayama A, Toshima N, inhibiting NF-κB mediated hyper inflammation. J Nanobiotechnol.
Miyamoto Y. Platinum nanoparticle is a useful scavenger of 2017;15(1):1–15. doi:10.1186/s12951-017-0252-y
superoxide anion and hydrogen peroxide. Free Radic Res. 64. Seisenbaeva GA, Fromell K, Vinogradov VV, et al. Dispersion of
2007;41(6):615–626. doi:10.1080/10715760601169679 TiO 2 nanoparticles improves burn wound healing and tissue
48. Mauricio MD, Guerra-Ojeda S, Marchio P, et al. Nanoparticles in regeneration through specific interaction with blood serum pro-
medicine: a focus on vascular oxidative stress. Oxid Med Cell teins. Sci Rep. 2017;7(1):1–11. doi:10.1038/s41598-017-15792-w
Longev. 2018;2018:6231482. doi:10.1155/2018/6231482 65. Fiorani L, Passacantando M, Santucci S, Di Marco S, Bisti S,
49. Singhal A, Morris VB, Labhasetwar V, Ghorpade A. Maccarone R. Cerium oxide nanoparticles reduce microglial activa-
Nanoparticle-mediated catalase delivery protects human neurons tion and neurodegenerative events in light damaged retina. PLoS
from oxidative stress. Cell Death Dis. 2013;4(11):e903–e903. One. 2015;10(10):e0140387. doi:10.1371/journal.pone.0140387
doi:10.1038/cddis.2013.362 66. Xue J, Liu T, Liu Y, et al. Neuroprotective effect of biosynthe-
50. Martín R, Menchón C, Apostolova N, et al. Nano-jewels in sised gold nanoparticles synthesised from root extract of Paeonia
biology. Gold and platinum on diamond nanoparticles as antiox- moutan against Parkinson disease – in vitro & In vivo model. J
idant systems against cellular oxidative stress. ACS Nano. 2010;4 Photochem Photobiol B. 2019;200:111635. doi:10.1016/j.
(11):6957–6965. doi:10.1021/nn1019412 jphotobiol.2019.111635
51. Milatovic D, Zaja-Milatovic S, Breyer RM, Aschner M, Montine 67. Park SY, Yi EH, Kim Y, Park G. Anti-neuroinflammatory effects
TJ. Chapter 64 - Neuroinflammation and oxidative injury in of Ephedra sinica Stapf extract-capped gold nanoparticles in
developmental neurotoxicity. In: Gupta RC, editor. Reproductive microglia. Int J Nanomedicine. 2019;14:2861. doi:10.2147/IJN.
and Developmental Toxicology. Academic Press; 2011:847–854. S195218
52. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular 68. Murad U, Khan SA, Ibrar M, Ullah S, Khattak U. Synthesis of
unit in health and disease. Pharmacol Rev. 2005;57(2):173–185. silver and gold nanoparticles from leaf of Litchi chinensis and its
doi:10.1124/pr.57.2.4 biological activities. Asian Pac J Trop Biomed. 2018;8(3):142.
53. Shih R-H, Wang C-Y, Yang C-M. NF-kappaB signaling pathways doi:10.4103/2221-1691.227995
in neurological inflammation: a mini review. Mini review. Front 69. Govindappa M, Hemashekhar B, Arthikala M-K, Ravishankar
Mol Neurosci. 2015;8(77). doi:10.3389/fnmol.2015.00077 Rai V, Ramachandra YL. Characterization, antibacterial, antiox-
54. Kim M-H, Jeong H-J. Zinc oxide nanoparticles suppress LPS- idant, antidiabetic, anti-inflammatory and antityrosinase activity
induced NF-κB activation by inducing A20, a negative regulator of green synthesized silver nanoparticles using Calophyllum
of NF-κB, in RAW 264.7 macrophages. J Nanosci Nanotechnol. tomentosum leaves extract. Results Phys. 2018;9:400–408.
2015;15(9):6509–6515. doi:10.1166/jnn.2015.10319 doi:10.1016/j.rinp.2018.02.049

DovePress

70. Erjaee H, Nazifi S, Rajaian H. Effect of Ag-NPs synthesised by 85. Iwai A, Masliah E, Yoshimoto M, et al. The precursor protein of
Chamaemelum nobile extract on the inflammation and oxidative non-Aβ component of Alzheimer’s disease amyloid is a presy-
stress induced by carrageenan in mice paw. IET Nanobiotechnol. naptic protein of the central nervous system. Neuron. 1995;14
2017;11(6):695–701. doi:10.1049/iet-nbt.2016.0245 (2):467–475. doi:10.1016/0896-6273(95)90302-X
71. Muniyappan N, Nagarajan NS. Green synthesis of silver nano- 86. Singleton A, Farrer M, Johnson J, et al. [alpha]-synuclein locus
particles with Dalbergia spinosa leaves and their applications in triplication causes Parkinson’s disease. science. 2003;302
biological and catalytic activities. Process Biochem. 2014;49 (5646):841–842. doi:10.1126/science.1090278
(6):1054–1061. doi:10.1016/j.procbio.2014.03.015 87. Sontheimer H. Diseases of the Nervous System. Academic Press;
72. David L, Moldovan B, Vulcu A, et al. Green synthesis, character- 2015.
ization and anti-inflammatory activity of silver nanoparticles 88. Wingo TS, Cutler DJ, Yarab N, Kelly CM, Glass JD. The herit-
using European black elderberry fruits extract. Colloids Surf B ability of amyotrophic lateral sclerosis in a clinically ascertained
Biointerfaces. 2014;122:767–777. doi:10.1016/j.colsurfb.2014. United States research registry. PLoS One. 2011;6(11):e27985.
08.018 doi:10.1371/journal.pone.0027985
73. Mohamed El-Rafie H, Abdel-Aziz Hamed M. Antioxidant and 89. Battistini S, Ricci C, Lotti EM, et al. Severe familial ALS with a
anti-inflammatory activities of silver nanoparticles biosynthesized novel exon 4 mutation (L106F) in the SOD1 gene. J Neurol Sci.
from aqueous leaves extracts of four Terminalia species. Adv Nat 2010;293(1–2):112–115. doi:10.1016/j.jns.2010.03.009
Sci: Nanosci Nanotechnol. 2014;5(3):035008. doi:10.1088/2043- 90. Parakh S, Atkin JD. Protein folding alterations in amyotrophic
6262/5/3/035008 lateral sclerosis. Brain Res. 2016;1648:633–649. doi:10.1016/j.
74. Wang Y, Li S-Y, Shen S, Wang J. Protecting neurons from brainres.2016.04.010
cerebral ischemia/reperfusion injury via nanoparticle-mediated 91. Robberecht W, Philips T. The changing scene of amyotrophic
delivery of an siRNA to inhibit microglial neurotoxicity. lateral sclerosis. Nat Rev Neurosci. 2013;14(4):248–264.
Biomaterials. 2018;161:95–105. doi:10.1016/j.biomaterials.2018. doi:10.1038/nrn3430
01.039 92. Sweeney P, Park H, Baumann M, et al. Protein misfolding in
75. Yuan X, Fu Z, Ji P, et al. Selenium nanoparticles pre-treatment neurodegenerative diseases: implications and strategies. Transl
reverse behavioral, oxidative damage, neuronal loss and neuro- Neurodegener. 2017;6(1):6. doi:10.1186/s40035-017-0077-5
chemical alterations in pentylenetetrazole-induced epileptic sei- 93. Gonzalez-Garcia M, Fusco G, De Simone A. Membrane inter-
zures in mice. Int J Nanomedicine. 2020;15:6339. doi:10.2147/ actions and toxicity by misfolded protein oligomers. Review.
IJN.S259134 Front Cell Dev Biol. 2021;9(395). doi:10.3389/fcell.2021.64
76. Andrabi SS, Yang J, Gao Y, Kuang Y, Labhasetwar V. 2623
Nanoparticles with antioxidant enzymes protect injured spinal 94. Folch J, Ettcheto M, Petrov D, et al. Review of the advances in
cord from neuronal cell apoptosis by attenuating mitochondrial treatment for Alzheimer disease: strategies for combating β-amy-
dysfunction. J Control Release. 2020;317:300–311. doi:10.1016/j. loid protein. Neurología (English Edition). 2018;33(1):47–58.
jconrel.2019.12.001 doi:10.1016/j.nrleng.2015.03.019
77. Nazarian S, Abdolmaleki Z, Torfeh A, Beheshtiha SHS. 95. Yang W, Wang L, Mettenbrink EM, DeAngelis PL, Wilhelm S.
Mesenchymal stem cells with modafinil (gold nanoparticles) sig- Nanoparticle toxicology. Annu Rev Pharmacol Toxicol. 2021;61
nificantly improves neurological deficits in rats after middle cere- (1):269–289. doi:10.1146/annurev-pharmtox-032320-110338
bral artery occlusion. Exp Brain Res. 2020;238(11):2589–2601. 96. Rivera Gil P, Oberdörster G, Elder A, Puntes V, Parak WJ.
doi:10.1007/s00221-020-05913-9 Correlating physico-chemical with toxicological properties of
78. Petro M, Jaffer H, Yang J, Kabu S, Morris VB, Labhasetwar V. nanoparticles: the present and the future. ACS Nano. 2010;4
Tissue plasminogen activator followed by antioxidant-loaded (10):5527–5531. doi:10.1021/nn1025687
nanoparticle delivery promotes activation/mobilization of pro- 97. Elsaesser A, Howard CV. Toxicology of nanoparticles. Adv Drug
genitor cells in infarcted rat brain. Biomaterials. 2016;81:169– Deliv Rev. 2012;64(2):129–137. doi:10.1016/j.addr.2011.09.001
180. doi:10.1016/j.biomaterials.2015.12.009 98. Fu PP, Xia Q, Hwang H-M, Ray PC, Yu H. Mechanisms of
79. Küçükdoğru R, Türkez H, Arslan ME, et al. Neuroprotective nanotoxicity: generation of reactive oxygen species. J Food
effects of boron nitride nanoparticles in the experimental Drug Anal. 2014;22(1):64–75. doi:10.1016/j.jfda.2014.01.005
Parkinson’s disease model against MPP+ induced apoptosis. 99. Chen KL, Bothun GD. Nanoparticles Meet Cell Membranes:
Metab Brain Dis. 2020;35(6):947–957. doi:10.1007/s11011-020- Probing Nonspecific Interactions Using Model Membranes.
00559-6 ACS Publications; 2014.
80. Puzzo D, Gulisano W, Palmeri A, Arancio O. Rodent models for 100. Nel A, Xia T, Mädler L, Li N. Toxic potential of materials at the
Alzheimer’s disease drug discovery. Expert Opin Drug Discov. nanolevel. science. 2006;311(5761):622–627. doi:10.1126/
2015;10(7):703–711. doi:10.1517/17460441.2015.1041913 science.1114397
81. Espay AJ, Vizcarra JA, Marsili L, et al. Revisiting protein aggre- 101. Abdal Dayem A, Hossain MK, Lee SB, et al. The role of reactive
gation as pathogenic in sporadic Parkinson and Alzheimer dis- oxygen species (ROS) in the biological activities of metallic
eases. Neurology. 2019;92(7):329–337. doi:10.1212/WNL.00 nanoparticles. Int J Mol Sci. 2017;18(1):120. doi:10.3390/
00000000006926 ijms18010120
82. Khanam H, Ali A, Asif M. Neurodegenerative diseases linked to 102. Xia T, Kovochich M, Brant J, et al. Comparison of the abilities of
misfolded proteins and their therapeutic approaches: a review. ambient and manufactured nanoparticles to induce cellular toxi-
Eur J Med Chem. 2016;124:1121–1141. doi:10.1016/j.ejmech. city according to an oxidative stress paradigm. Nano Lett. 2006;6
2016.08.006 (8):1794–1807. doi:10.1021/nl061025k
83. Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of 103. Teleanu DM, Chircov C, Grumezescu AM, Teleanu RI.
Alzheimer’s disease: from genetic to non-genetic factors. Curr Neurotoxicity of nanomaterials: an up-to-date overview.
Alzheimer Res. 2013;10(8):852–867. doi:10.2174/15672050113 Nanomaterials (Basel). 2019;9(1):96. doi:10.3390/nano9010096
109990155 104. Yuan ZY, Hu YL, Gao JQ. Brain localization and neurotoxicity
84. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegenera- evaluation of polysorbate 80-modified chitosan nanoparticles in
tion: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev rats. PLoS One. 2015;10(8):e0134722. doi:10.1371/journal.pone.
Mol Cell Biol. 2007;8(2):101–112. doi:10.1038/nrm2101 0134722

327
DovePress

105. Huo T, Barth RF, Yang W, et al. Preparation, biodistribution and 122. Cerqueira SR, Ayad NG, Lee JK. Neuroinflammation treatment
neurotoxicity of liposomal cisplatin following convection via targeted delivery of nanoparticles. Front Cell Neurosci.
enhanced delivery in normal and F98 glioma bearing rats. PLoS 2020;14:576037. doi:10.3389/fncel.2020.576037
One. 2012;7(11):e48752–e48752. doi:10.1371/journal.pone.0048 123. Weller J, Budson A. Current understanding of Alzheimer’s dis-
752 ease diagnosis and treatment. F1000Research. 2018;7:1161.
106. Zeng Y, Kurokawa Y, Win-Shwe TT, et al. Effects of PAMAM doi:10.12688/f1000research.14506.1
dendrimers with various surface functional groups and multiple 124. Teixeira MI, Lopes CM, Amaral MH, Costa PC. Current insights
generations on cytotoxicity and neuronal differentiation using on lipid nanocarrier-assisted drug delivery in the treatment of
human neural progenitor cells. J Toxicol Sci. 2016;41(3):351– neurodegenerative diseases. Eur J Pharm Biopharm.
370. doi:10.2131/jts.41.351 2020;149:192–217. doi:10.1016/j.ejpb.2020.01.005
107. Yarjanli Z, Ghaedi K, Esmaeili A, Rahgozar S, Zarrabi A. Iron 125. López ES, Machado AL, Vidal LB, González-Pizarro R, Silva
oxide nanoparticles may damage to the neural tissue through iron AD, Souto EB. Lipid nanoparticles as carriers for the treatment of
accumulation, oxidative stress, and protein aggregation. BMC neurodegeneration associated with Alzheimer’s disease and glau-
Neurosci. 2017;18(1):51. doi:10.1186/s12868-017-0369-9 coma: present and future challenges. Curr Pharm Des. 2020;26
108. Sun C, Yin N, Wen R, et al. Silver nanoparticles induced neuro- (12):1235–1250. doi:10.2174/1381612826666200218101231
toxicity through oxidative stress in rat cerebral astrocytes is dis- 126. Loureiro JA, Andrade S, Duarte A, et al. Resveratrol and grape
tinct from the effects of silver ions. Neurotoxicology. extract-loaded solid lipid nanoparticles for the treatment of
2016;52:210–221. doi:10.1016/j.neuro.2015.09.007 Alzheimer’s disease. Molecules. 2017;22(2):277. doi:10.3390/
109. You R, Ho Y-S, Hung CH-L, et al. Silica nanoparticles induce molecules22020277
neurodegeneration-like changes in behavior, neuropathology, and 127. Rajput A, Bariya A, Allam A, Othman S, Butani SB. In situ
affect synapse through MAPK activation. Part Fibre Toxicol. nanostructured hydrogel of resveratrol for brain targeting: in
2018;15(1):28. doi:10.1186/s12989-018-0263-3 vitro-in vivo characterization. Drug Deliv Transl Res. 2018;8
110. Shi B, Du X, Chen J, et al. Multifunctional hybrid nanoparticles (5):1460–1470. doi:10.1007/s13346-018-0540-6
for traceable drug delivery and intracellular microenvironment- 128. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.
controlled multistage drug-release in neurons. Small. 2017;13 Bioavailability of curcumin: problems and promises. Mol
(20):1603966. doi:10.1002/smll.201603966 Pharm. 2007;4(6):807–818. doi:10.1021/mp700113r
111. Song B, Zhang Y, Liu J, Feng X, Zhou T, Shao L. Unraveling the 129. Cheng KK, Yeung CF, Ho SW, Chow SF, Chow AH, Baum L. Highly
neurotoxicity of titanium dioxide nanoparticles: focusing on stabilized curcumin nanoparticles tested in an in vitro blood–brain
molecular mechanisms. Beilstein J Nanotechnol. 2016;7:645– barrier model and in Alzheimer’s disease Tg2576 mice. AAPS J.
654. doi:10.3762/bjnano.7.57 2013;15(2):324–336. doi:10.1208/s12248-012-9444-4
112. Zhao Y, Wang X, Wu Q, Li Y, Wang D. Translocation and 130. Mandal M, Jaiswal P, Mishra A. Role of curcumin and its nano-
neurotoxicity of CdTe quantum dots in RMEs motor neurons in formulations in neurotherapeutics: a comprehensive review. J
nematode Caenorhabditis elegans. J Hazard Mater. 2015;28 Biochem Mol Toxicol. 2020;34(6):e22478. doi:10.1002/jbt.22478
3:480–489. doi:10.1016/j.jhazmat.2014.09.063 131. Doggui S, Sahni JK, Arseneault M, Dao L, Ramassamy C. Neuronal
113. Wu T, Zhang T, Chen Y, Tang M. Research advances on potential uptake and neuroprotective effect of curcumin-loaded PLGA nano-
neurotoxicity of quantum dots. J Appl Toxicol. 2016;36(3):345– particles on the human SK-N-SH cell line. J Alzheimers Dis. 2012;30
351. doi:10.1002/jat.3229 (2):377–392. doi:10.3233/JAD-2012-112141
114. Ceña V, Játiva P. Nanoparticle crossing of blood–brain barrier: a 132. Barbara R, Belletti D, Pederzoli F, et al. Novel curcumin loaded
road to new therapeutic approaches to central nervous system nanoparticles engineered for blood-brain barrier crossing and able
diseases. Future Med. 2018;13(13):1513–1516. to disrupt Abeta aggregates. Int J Pharm. 2017;526(1–2):413–
115. Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino 424. doi:10.1016/j.ijpharm.2017.05.015
L. Nanoparticle-mediated brain drug delivery: overcoming blood– 133. Tiwari SK, Agarwal S, Seth B, et al. Curcumin-loaded nanopar-
brain barrier to treat neurodegenerative diseases. J Control ticles potently induce adult neurogenesis and reverse cognitive
Release. 2016;235:34–47. doi:10.1016/j.jconrel.2016.05.044 deficits in Alzheimer’s disease model via canonical Wnt/β-catenin
116. Zhou Y, Peng Z, Seven ES, Leblanc RM. Crossing the blood- pathway. ACS Nano. 2014;8(1):76–103. doi:10.1021/nn405077y
brain barrier with nanoparticles. J Control Release. 134. Fan S, Zheng Y, Liu X, et al. Curcumin-loaded PLGA-PEG
2018;270:290–303. doi:10.1016/j.jconrel.2017.12.015 nanoparticles conjugated with B6 peptide for potential use in
117. Ding S, Khan AI, Cai X, et al. Overcoming blood–brain barrier Alzheimer’s disease. Drug Deliv. 2018;25(1):1091–1102.
transport: advances in nanoparticle-based drug delivery strategies. doi:10.1080/10717544.2018.1461955
Mater Today. 2020;37:112–125. doi:10.1016/j.mattod.2020.02.001 135. Lazar AN, Mourtas S, Youssef I, et al. Curcumin-conjugated
118. Pardridge WM. The blood-brain barrier: bottleneck in brain drug nanoliposomes with high affinity for Aβ deposits: possible appli-
development. NeuroRx. 2005;2(1):3–14. doi:10.1602/neurorx. cations to Alzheimer disease. Nanomedicine. 2013;9(5):712–721.
2.1.3 doi:10.1016/j.nano.2012.11.004
119. Reimold I, Domke D, Bender J, Seyfried CA, Radunz H-E, 136. Md S, Gan SY, Haw YH, Ho CL, Wong S, Choudhury H. In vitro
Fricker G. Delivery of nanoparticles to the brain detected by neuroprotective effects of naringenin nanoemulsion against β-
fluorescence microscopy. Eur J Pharm Biopharm. 2008;70 amyloid toxicity through the regulation of amyloidogenesis and
(2):627–632. doi:10.1016/j.ejpb.2008.05.007 tau phosphorylation. Int J Biol Macromol. 2018;118:1211–1219.
120. Fornaguera C, Dols-Perez A, Caldero G, Garcia-Celma M, doi:10.1016/j.ijbiomac.2018.06.190
Camarasa J, Solans C. PLGA nanoparticles prepared by nano- 137. Puerta E, Suárez-Santiago JE, Santos-Magalhães NS, Ramirez
emulsion templating using low-energy methods as efficient nano- MJ, Irache JM. Effect of the oral administration of nanoencapsu-
carriers for drug delivery across the blood–brain barrier. J Control lated quercetin on a mouse model of Alzheimer’s disease. Int J
Release. 2015;211:134–143. doi:10.1016/j.jconrel.2015.06.002 Pharm. 2017;517(1–2):50–57. doi:10.1016/j.ijpharm.2016.11.061
121. Sahni JK, Doggui S, Ali J, Baboota S, Dao L, Ramassamy C. 138. Testa G, Gamba P, Badilli U, et al. Loading into nanoparticles
Neurotherapeutic applications of nanoparticles in Alzheimer’s improves quercetin’s efficacy in preventing neuroinflammation
disease. J Control Release. 2011;152(2):208–231. doi:10.1016/j. induced by oxysterols. PLoS One. 2014;9(5):e96795. doi:10.
jconrel.2010.11.033 1371/journal.pone.0096795

DovePress

139. Palle S, Neerati P. Quercetin nanoparticles attenuates scopolamine 154. Al Asmari AK, Ullah Z, Tariq M, Fatani A. Preparation, char-
induced spatial memory deficits and pathological damages in rats. acterization, and in vivo evaluation of intranasally administered
Bull Fac Pharm Cairo Univ. 2017;55(1):101–106. doi:10.1016/j. liposomal formulation of donepezil. Drug Des Devel Ther.
bfopcu.2016.10.004 2016;10:205. doi:10.2147/DDDT.S93937
140. Sun D, Li N, Zhang W, et al. Design of PLGA-functionalized 155. Misra S, Chopra K, Sinha V, Medhi B. Galantamine-loaded solid–
quercetin nanoparticles for potential use in Alzheimer’s disease. lipid nanoparticles for enhanced brain delivery: preparation, char-
Colloids Surf B Biointerfaces. 2016;148:116–129. doi:10.1016/j. acterization, in vitro and in vivo evaluations. Drug Deliv. 2016;23
colsurfb.2016.08.052 (4):1434–1443. doi:10.3109/10717544.2015.1089956
141. Kuo Y-C, Rajesh R. Targeted delivery of rosmarinic acid across 156. Sánchez-López E, Ettcheto M, Egea MA, et al. Memantine loaded
the blood–brain barrier for neuronal rescue using polyacrylamide- PLGA PEGylated nanoparticles for Alzheimer’s disease: in vitro
chitosan-poly (lactide-co-glycolide) nanoparticles with surface and in vivo characterization. J Nanobiotechnology. 2018;16(1):1–
cross-reacting material 197 and apolipoprotein E. Int J Pharm. 16. doi:10.1186/s12951-018-0356-z
2017;528(1–2):228–241. doi:10.1016/j.ijpharm.2017.05.039 157. Jamshed N, Ozair FF, Aggarwal P, Ekka M. Alzheimer disease in
142. Smith A, Giunta B, Bickford PC, Fountain M, Tan J, Shytle RD. post-menopausal women: intervene in the critical window period.
Nanolipidic particles improve the bioavailability and α-secretase J Midlife Health. 2014;5(1):38. doi:10.4103/0976-7800.127791
inducing ability of epigallocatechin-3-gallate (EGCG) for the 158. Mittal G, Carswell H, Brett R, Currie S, Kumar MR.
treatment of Alzheimer’s disease. Int J Pharm. 2010;389(1– Development and evaluation of polymer nanoparticles for oral
2):207–212. doi:10.1016/j.ijpharm.2010.01.012 delivery of estradiol to rat brain in a model of Alzheimer’s
143. Singh NA, Mandal AKA, Khan ZA. Inhibition of Al (III)-induced pathology. J Control Release. 2011;150(2):220–228.
Aβ 42 fibrillation and reduction of neurotoxicity by epigallocate- doi:10.1016/j.jconrel.2010.11.013
chin-3-gallate nanoparticles. J Biomed Nanotechnol. 2018;14 159. Wilcock GK, Black SE, Hendrix SB, et al. Efficacy and safety of
(6):1147–1158. doi:10.1166/jbn.2018.2552 tarenflurbil in mild to moderate Alzheimer’s disease: a rando-
144. Zhang J, Zhou X, Yu Q, et al. Epigallocatechin-3-gallate mised phase II trial. Lancet Neurol. 2008;7(6):483–493.
(EGCG)-stabilized selenium nanoparticles coated with Tet-1 pep- doi:10.1016/S1474-4422(08)70090-5
tide to reduce amyloid-β aggregation and cytotoxicity. ACS Appl 160. Muntimadugu E, Dhommati R, Jain A, Challa VGS, Shaheen M,
Mater Interfaces. 2014;6(11):8475–8487. doi:10.1021/am50 Khan W. Intranasal delivery of nanoparticle encapsulated taren-
1341u flurbil: a potential brain targeting strategy for Alzheimer’s dis-
145. Parihar VK, Prabhakar K, Veerapur VP, et al. Effect of sesamol ease. Eur J Pharm Sci. 2016;92:224–234. doi:10.1016/j.
on radiation-induced cytotoxicity in Swiss albino mice. Mutat Res ejps.2016.05.012
Genet Toxicol Environ Mutagen. 2006;611(1–2):9–16. doi:10.10 161. Poovaiah N, Davoudi Z, Peng H, et al. Treatment of neurodegen-
16/j.mrgentox.2006.06.037 erative disorders through the blood-brain barrier using nanocarriers.
146. Sachdeva AK, Misra S, Kaur IP, Chopra K. Neuroprotective Nanoscale. 2018;10(36):16962–16983. doi:10.1039/c8nr04073g
potential of sesamol and its loaded solid lipid nanoparticles in 162. Zhang C, Chen J, Feng C, et al. Intranasal nanoparticles of basic
ICV-STZ-induced cognitive deficits: behavioral and biochemical fibroblast growth factor for brain delivery to treat Alzheimer’s
evidence. Eur J Pharmacol. 2015;747:132–140. doi:10.1016/j. disease. Int J Pharm. 2014;461(1–2):192–202. doi:10.1016/j.
ejphar.2014.11.014 ijpharm.2013.11.049
147. Cai Z, Wang C, Yang W. Role of berberine in Alzheimer’s 163. Fakhri S, Abdian S, Zarneshan SN, Akkol EK, Farzaei MH,
disease. Neuropsychiatr Dis Treat. 2016;12:2509. doi:10.2147/ Sobarzo-Sánchez E. Targeting mitochondria by plant secondary
NDT.S114846 metabolites: a promising strategy in combating Parkinson’s disease.
148. Lohan S, Raza K, Mehta S, Bhatti GK, Saini S, Singh B. Anti- Int J Mol Sci. 2021;22(22):12570. doi:10.3390/ijms222212570
Alzheimer’s potential of berberine using surface decorated multi- 164. Palle S, Neerati P. Improved neuroprotective effect of resveratrol
walled carbon nanotubes: a preclinical evidence. Int J Pharm. nanoparticles as evinced by abrogation of rotenone-induced beha-
2017;530(1–2):263–278. doi:10.1016/j.ijpharm.2017.07.080 vioral deficits and oxidative and mitochondrial dysfunctions in rat
149. Meng Q, Wang A, Hua H, et al. Intranasal delivery of Huperzine model of Parkinson’s disease. Naunyn Schmiedebergs Arch
A to the brain using lactoferrin-conjugated N-trimethylated chit- Pharmacol. 2018;391(4):445–453. doi:10.1007/s00210-018-1474-8
osan surface-modified PLGA nanoparticles for treatment of 165. Wang M, Li L, Zhang X, et al. Magnetic resveratrol liposomes as a
Alzheimer’s disease. Int J Nanomedicine. 2018;13:705. doi:10. new theranostic platform for magnetic resonance imaging guided
2147/IJN.S151474 Parkinson’s disease targeting therapy. ACS Sustain Chem Eng.
150. Aalinkeel R, Kutscher HL, Singh A, et al. Neuroprotective effects 2018;6(12):17124–17133. doi:10.1021/acssuschemeng.8b04507
of a biodegradable poly (lactic-co-glycolic acid)-ginsenoside Rg3 166. Pangeni R, Sharma S, Mustafa G, Ali J, Baboota S. Vitamin E loaded
nanoformulation: a potential nanotherapy for Alzheimer’s dis- resveratrol nanoemulsion for brain targeting for the treatment of
ease? J Drug Target. 2018;26(2):182–193. doi:10.1080/1061 Parkinson’s disease by reducing oxidative stress. Nanotechnology.
186X.2017.1354002 2014;25(48):485102. doi:10.1088/0957-4484/25/48/485102
151. Dara T, Vatanara A, Meybodi MN, et al. Erythropoietin-loaded 167. da Rocha Lindner G, Bonfanti Santos D, Colle D, et al. Improved
solid lipid nanoparticles: preparation, optimization, and in vivo neuroprotective effects of resveratrol-loaded polysorbate 80-coated
evaluation. Colloids Surf B Biointerfaces. 2019;178:307–316. poly (lactide) nanoparticles in MPTP-induced Parkinsonism.
doi:10.1016/j.colsurfb.2019.01.027 Nanomedicine. 2015;10(7):1127–1138. doi:10.2217/nnm.14.165
152. Ismail MF, ElMeshad AN, Salem NA-H. Potential therapeutic 168. Kundu P, Das M, Tripathy K, Sahoo SK. Delivery of dual drug
effect of nanobased formulation of rivastigmine on rat model of loaded lipid based nanoparticles across the blood–brain barrier
Alzheimer’s disease. Int J Nanomedicine. 2013;8:393. doi:10.21 impart enhanced neuroprotection in a rotenone induced mouse
47/IJN.S39232 model of Parkinson’s disease. ACS Chem Neurosci. 2016;7
153. Shah B, Khunt D, Bhatt H, Misra M, Padh H. Application of (12):1658–1670. doi:10.1021/acschemneuro.6b00207
quality by design approach for intranasal delivery of rivastigmine 169. Gaba B, Khan T, Haider MF, et al. Vitamin E loaded naringenin
loaded solid lipid nanoparticles: effect on formulation and char- nanoemulsion via intranasal delivery for the management of
acterization parameters. Eur J Pharm Sci. 2015;78:54–66. oxidative stress in a 6-OHDA Parkinson’s disease model.
doi:10.1016/j.ejps.2015.07.002 Biomed Res Int. 2019;2019:1–20. doi:10.1155/2019/2382563

329
DovePress

170. Burgos RA, Alarcón P, Quiroga J, Manosalva C, Hancke J. 187. Wang J, Xu G, Gonzales V, et al. Fibrillar inclusions and motor
Andrographolide, an anti-inflammatory multitarget drug: all neuron degeneration in transgenic mice expressing superoxide
roads lead to cellular metabolism. Molecules. 2020;26(1):5. dismutase 1 with a disrupted copper-binding site. Neurobiol Dis.
doi:10.3390/molecules26010005 2002;10(2):128–138. doi:10.1006/nbdi.2002.0498
171. Md S, Khan RA, Mustafa G, et al. Bromocriptine loaded chitosan 188. Bhatia NK, Srivastava A, Katyal N, et al. Curcumin binds to the
nanoparticles intended for direct nose to brain delivery: pharma- pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1)
codynamic, pharmacokinetic and scintigraphy study in mice and alters its amyloidogenic pathway resulting in reduced cyto-
model. Eur J Pharm Sci. 2013;48(3):393–405. doi:10.1016/j. toxicity. Biochim Biophys Acta Proteins Proteom. 2015;1854
ejps.2012.12.007 (5):426–436. doi:10.1016/j.bbapap.2015.01.014
172. Yang X, Zheng R, Cai Y, Liao M, Yuan W, Liu Z. Controlled- 189. Tripodo G, Chlapanidas T, Perteghella S, et al. Mesenchymal
release levodopa methyl ester/benserazide-loaded nanoparticles stromal cells loading curcumin-INVITE-micelles: a drug delivery
ameliorate levodopa-induced dyskinesia in rats. Int J system for neurodegenerative diseases. Colloids Surf B
Nanomedicine. 2012;7:2077. doi:10.2147/IJN.S30463 Biointerfaces. 2015;125:300–308. doi:10.1016/j.colsurfb.2014.11.
173. Lim JH, Kim SS, Boo DH, et al. Protective effect of bromocrip- 034
tine against BH4-induced Cath. a cell death involving up-regula- 190. Rothstein JD. Edaravone: a new drug approved for ALS. Cell.
tion of antioxidant enzymes. Neurosci Lett. 2009;451(3):185–189. 2017;171(4):725. doi:10.1016/j.cell.2017.10.011
174. Esposito E, Fantin M, Marti M, et al. Solid lipid nanoparticles as 191. Yang T, Ferrill L, Gallant L, et al. Verapamil and riluzole cocktail
delivery systems for bromocriptine. Pharm Res. 2008;25 liposomes overcome pharmacoresistance by inhibiting
(7):1521–1530. doi:10.1007/s11095-007-9514-y P-glycoprotein in brain endothelial and astrocyte cells: a potent
175. Barcia E, Boeva L, García-García L, et al. Nanotechnology-based approach to treat amyotrophic lateral sclerosis. Eur J Pharm Sci.
drug delivery of ropinirole for Parkinson’s disease. Drug Deliv. 2018;120:30–39. doi:10.1016/j.ejps.2018.04.026
2017;24(1):1112–1123. doi:10.1080/10717544.2017.1359862 192. Silva Adaya D, Aguirre-Cruz L, Guevara J, Ortiz-Islas E.
176. Fukuzaki K, Kamenosono T, Nagata R. Effects of ropinirole on Nanobiomaterials’ applications in neurodegenerative diseases. J
various parkinsonian models in mice, rats, and cynomolgus mon- Biomater Appl. 2017;31(7):953–984. doi:10.1177/0885328216
keys. Pharmacol Biochem Behav. 2000;65(3):503–508. doi:10. 659032
1016/S0091-3057(99)00240-3 193. Battaglia L, Panciani PP, Muntoni E, et al. Lipid nanoparticles for
177. Pardeshi CV, Belgamwar VS, Tekade AR, Surana SJ. Novel sur- intranasal administration: application to nose-to-brain delivery.
face modified polymer–lipid hybrid nanoparticles as intranasal Expert Opin Drug Deliv. 2018;15(4):369–378. doi:10.1080/
carriers for ropinirole hydrochloride: in vitro, ex vivo and in 17425247.2018.1429401
vivo pharmacodynamic evaluation. J Mater Sci Mater Med. 194. Marcuzzo S, Isaia D, Bonanno S, et al. FM19G11-loaded gold
2013;24(9):2101–2115. doi:10.1007/s10856-013-4965-7 nanoparticles enhance the proliferation and self-renewal of epen-
178. Raj R, Wairkar S, Sridhar V, Gaud R. Pramipexole dihydrochloride dymal stem progenitor cells derived from ALS mice. Cells.
loaded chitosan nanoparticles for nose to brain delivery: develop- 2019;8(3):279. doi:10.3390/cells8030279
ment, characterization and in vivo anti-Parkinson activity. Int J Biol 195. Nouri Z, Fakhri S, El-Senduny FF, et al. On the
Macromol. 2018;109:27–35. doi:10.1016/j.ijbiomac.2017.12.056 neuroprotective effects of naringenin: pharmacological tar-
179. Subramony JA. Apomorphine in dopaminergic therapy. Mol gets, signaling pathways, molecular mechanisms, and clinical
Pharm. 2006;3(4):380–385. doi:10.1021/mp060012c perspective. Biomolecules. 2019;9(11):690. doi:10.3390/
180. Tsai M-J, Huang Y-B, Wu P-C, et al. Oral apomorphine delivery biom9110690
from solid lipid nanoparticles with different monostearate emul- 196. Lu X, Dong J, Zheng D, Li X, Ding D, Xu H. Reperfusion combined
sifiers: pharmacokinetic and behavioral evaluations. J Pharm Sci. with intraarterial administration of resveratrol-loaded nanoparticles
2011;100(2):547–557. doi:10.1002/jps.22285 improved cerebral ischemia–reperfusion injury in rats.
181. Kumar S, Dang S, Nigam K, Ali J, Baboota S. Selegiline nanofor- Nanomedicine. 2020;28:102208. doi:10.1016/j.nano.2020.102208
mulation in attenuation of oxidative stress and upregulation of 197. Kakkar V, Muppu SK, Chopra K, Kaur IP. Curcumin loaded solid
dopamine in the brain for the treatment of Parkinson’s disease. lipid nanoparticles: an efficient formulation approach for cerebral
Rejuvenation Res. 2018;21(5):464–476. doi:10.1089/rej.2017.2035 ischemic reperfusion injury in rats. Eur J Pharm Biopharm.
182. Kumar S, Ali J, Baboota S. Design Expert® supported optimiza- 2013;85(3):339–345. doi:10.1016/j.ejpb.2013.02.005
tion and predictive analysis of selegiline nanoemulsion via the 198. Ghosh A, Sarkar S, Mandal AK, Das N. Neuroprotective
olfactory region with enhanced behavioural performance in role of nanoencapsulated quercetin in combating ischemia-
Parkinson’s disease. Nanotechnology. 2016;27(43):435101. reperfusion induced neuronal damage in young and aged
doi:10.1088/0957-4484/27/43/435101 rats. PLoS One. 2013;8(4):e57735. doi:10.1371/journal.pone.
183. Rinaldi F, Seguella L, Gigli S, et al. inPentasomes: an innovative 0057735
nose-to-brain pentamidine delivery blunts MPTP parkinsonism in 199. Ghosh S, Sarkar S, Choudhury ST, Ghosh T, Das N. Triphenyl
mice. J Control Release. 2019;294:17–26. doi:10.1016/j.jconrel. phosphonium coated nano-quercetin for oral delivery: neuropro-
2018.12.007 tective effects in attenuating age related global moderate cerebral
184. Velander P, Wu L, Henderson F, Zhang S, Bevan DR, Xu B. ischemia reperfusion injury in rats. Nanomedicine. 2017;13
Natural product-based amyloid inhibitors. Biochem Pharmacol. (8):2439–2450. doi:10.1016/j.nano.2017.08.002
2017;139:40–55. doi:10.1016/j.bcp.2017.04.004 200. Zhang J, Han X, Li X, et al. Core-shell hybrid liposomal vesicles
185. Bondi M, Montana G, Craparo E, et al. Ferulic acid-loaded lipid loaded with panax notoginsenoside: preparation, characterization
nanostructures as drug delivery systems for Alzheimer’s disease: and protective effects on global cerebral ischemia/reperfusion
preparation, characterization and cytotoxicity studies. Curr injury and acute myocardial ischemia in rats. Int J
Nanosci. 2009;5(1):26–32. doi:10.2174/157341309787314656 Nanomedicine. 2012;7:4299. doi:10.2147/IJN.S32385
186. Mohammad-Beigi H, Morshedi D, Shojaosadati SA, et al. Gallic 201. Ahmad A, Fauzia E, Kumar M, et al. Gelatin-coated polycapro-
acid loaded onto polyethylenimine-coated human serum albumin lactone nanoparticle-mediated naringenin delivery rescue human
nanoparticles (PEI-HSA-GA NPs) stabilizes α-synuclein in the mesenchymal stem cells from oxygen glucose deprivation-
unfolded conformation and inhibits aggregation. RSC Adv. 2016;6 induced inflammatory stress. ACS Biomater Sci Eng. 2018;5
(88):85312–85323. (2):683–695. doi:10.1021/acsbiomaterials.8b01081

DovePress

202. Deng J, Mei H, Shi W, et al. Recombinant tissue plasminogen 212. Pepe G, Calce E, Verdoliva V, et al. Curcumin-loaded nano-
activator-conjugated nanoparticles effectively targets thromboly- particles based on amphiphilic hyaluronan-conjugate
sis in a rat model of middle cerebral artery occlusion. Curr Med explored as targeting delivery system for neurodegenerative
Sci. 2018;38(3):427–435. doi:10.1007/s11596-018-1896-z disorders. Int J Mol Sci. 2020;21(22):8846. doi:10.3390/
203. Fukuta T, Asai T, Yanagida Y, et al. Combination therapy with ijms21228846
liposomal neuroprotectants and tissue plasminogen activator for 213. Bhatt R, Singh D, Prakash A, Mishra N. Development, character-
treatment of ischemic stroke. FASEB J. 2017;31(5):1879–1890. ization and nasal delivery of rosmarinic acid-loaded solid lipid
doi:10.1096/fj.201601209R nanoparticles for the effective management of Huntington’s dis-
204. Zhu FD, Hu YJ, Yu L, et al. Nanoparticles: a hope for the ease. Drug Deliv. 2015;22(7):931–939. doi:10.3109/10717544.
treatment of inflammation in CNS. Front Pharmacol. 2014.880860
2021;12:683935. doi:10.3389/fphar.2021.683935 214. Dolati S, Babaloo Z, Jadidi-Niaragh F, Ayromlou H, Sadreddini
205. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. S, Yousefi M. Multiple sclerosis: therapeutic applications of
2005;438(7070):932–936. doi:10.1038/nature04478 advancing drug delivery systems. Biomed Pharmacother.
206. George ML, Eccles SA, Tutton MG, Abulafi AM, Swift RI. 2017;86:343–353. doi:10.1016/j.biopha.2016.12.010
Correlation of plasma and serum vascular endothelial growth factor 215. Kumar P, Sharma G, Gupta V, et al. Preclinical explorative
levels with platelet count in colorectal cancer: clinical evidence of assessment of dimethyl fumarate-based biocompatible nanolipoi-
platelet scavenging? Clin Cancer Res. 2000;6(8):3147–3152. dal carriers for the management of multiple sclerosis. ACS Chem
207. Ju R, Wen Y, Gou R, Wang Y, Xu Q. The experimental therapy on
Neurosci. 2018;9(5):1152–1158. doi:10.1021/acschemneuro.7b00
brain ischemia by improvement of local angiogenesis with tissue
519
engineering in the mouse. Cell Transplant. 2014;23(1_suppl):83–
216. Kumar P, Sharma G, Kumar R, et al. Vitamin-derived nanolipoi-
95. doi:10.3727/096368914X684998
dal carriers for brain delivery of dimethyl fumarate: a novel
208. Zhao H, Bao X-J, Wang R-Z, et al. Postacute ischemia vascular
approach with preclinical evidence. ACS Chem Neurosci. 2017;8
endothelial growth factor transfer by transferrin-targeted liposomes
(6):1390–1396. doi:10.1021/acschemneuro.7b00041
attenuates ischemic brain injury after experimental stroke in rats. Hum
217. Esposito E, Cortesi R, Drechsler M, et al. Nanoformulations for
Gene Ther. 2011;22(2):207–215. doi:10.1089/hum.2010.111
dimethyl fumarate: physicochemical characterization and in vitro/
209. Andre EM, Passirani C, Seijo B, Sanchez A, Montero-Menei CN.
in vivo behavior. Eur J Pharm Biopharm. 2017;115:285–296.
Nano and microcarriers to improve stem cell behaviour for neu-
roregenerative medicine strategies: application to Huntington’s doi:10.1016/j.ejpb.2017.04.011
disease. Biomaterials. 2016;83:347–362. doi:10.1016/j. 218. Yang J, Wang L, Huang L, et al. Receptor-targeting Nanomaterials
biomaterials.2015.12.008 Alleviate Binge Drinking-induced Neurodegeneration as Artificial
210. Maiti P, Dunbar GL. Use of curcumin, a natural polyphenol for Neurotrophins. Wiley Online Library; 2021:61–74.
targeting molecular pathways in treating age-related neurodegen- 219. Min HS, Kim HJ, Naito M, et al. Systemic brain delivery of
erative diseases. Int J Mol Sci. 2018;19(6):1637. doi:10.3390/ antisense oligonucleotides across the blood–brain barrier with a
ijms19061637 glucose-coated polymeric nanocarrier. Angew Chem. 2020;132
211. Sandhir R, Yadav A, Mehrotra A, Sunkaria A, Singh A, Sharma (21):8250–8257. doi:10.1002/ange.201914751
S. Curcumin nanoparticles attenuate neurochemical and neurobe- 220. Chang X, Li J, Niu S, Xue Y, Tang M. Neurotoxicity of metal-
havioral deficits in experimental model of Huntington’s disease. containing nanoparticles and implications in glial cells. J Appl
Neuromolecular Med. 2014;16(1):106–118. doi:10.1007/s12017- Toxicol. 2021;41(1):65–81. doi:10.1002/jat.4037
013-8261-y
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Nanoparticles in Combating Neuronal

Sajad Fakhri, Sadaf Abdian, Seyede Nazanin Zarneshan, Seyed Zachariah

To link to this article: https://doi.org/10.2147/IJN.S347187

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Nanoparticles in Combating Neuronal Dysregulated

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Figure 1 Dysregulated signaling pathways in NDDs.

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PLGA In vitro: SK-N-SH cells, a human ↑curcumin stability [131]

PLGA-PEG-B6 In vitro: HT22 cells ↑cellular absorption, ↑blood compatibility [134]

In vivo: APP/PS1 mice ↑spatial learning and memory performance [134]

Ex vivo ↓hippocampus-amyloid production and deposit, ↓tau hyperphosphorylation [134]

PLGA In vitro: rat hippocampal cells ↓Aβ aggregates [132]

PLGA-NPs In vivo: APP/PS1 mice ↑cognitive functions and memory [140]

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Disease Component Nano Vehicle/Method Study Type Results References

Nanoformulations of synthetic drugs

Donepezil Liposome In vivo: male Wistar rats ↑brain bioavailability [154]

Estradiol PLGA In vivo: male Sprague–Dawley ↑brain estradiol levels [158]

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Nanoformulations of Synthetic Drugs

Levodopa NPs In vitro/ in vivo ↓dyskinesia [172]

Ropinirole PLGA In vitro/ in vivo: male Wistar rats ↓neurodegeneration [175]

cell line depletion

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motor coordination impairment, and prevent dopaminergic

↓neuroinflammation, ↑dopaminergic neuronal function via blocking effect on glial-