Singh and Srivastava, IJPSR, 2019; Vol. 10(6): 2654-2662.

E-ISSN: 0975-8232; P-ISSN: 2320-5148

IJPSR (2019), Volume 10, Issue 6 (Review Article)

Received on 17 November 2018; received in revised form, 30 April 2019; accepted, 01 May 2019; published 01 June 2019

PARKINSONISM: A GENERAL MOTOR DISABILITY

Rishabh Singh and Anant Srivastava *
Hygia Institute of Pharmaceutical Education and Research, Lucknow - 226020, Uttar Pradesh, India.
Keywords: ABSTRACT: Parkinson’s disease (PD) is one of the most common
Parkinson’s disease (PD),
neurodegenerative disorders in the population above 60 years of age. The
Substantia nigra pars compacta movement abnormalities in PD are credited due to an imbalance between the
(SNpc), Ubiquitin-Proteasome System acetylcholine and dopamine which results in uncontrolled movements. It is
(UPS) characterized using resting tremor, postural impairment, bradykinesia, and
Correspondence to Author: rigidity. The degeneration of midbrain dopaminergic neurons and accumulation
Anant Srivastava of inclusions containing α-synuclein (termed “Lewy bodies”) throughout the
nervous system are few of the most prominent features of PD. Still, there is no
Assistant Professor, cure; we have several management options for the early treatment of PD. Several
Hygia Institute of Pharmaceutical objective methods have been proposed for improving the diagnostic accuracy of
Education and Research, Lucknow - PD, for enabling earlier diagnosis, to quantify the severity of disease and
226020, Uttar Pradesh, India.
progress of treatment given. These methods include motor performance tests,
E-mail: anantsrivastava88@gmail.com olfaction tests, imaging techniques, and biochemical tests of blood and
cerebrospinal fluid. None of the proposed methods is widely available or
clinically used for PD. The validation of the objective methods takes time, and a
large number of regulatory requirements need to be considered before a new
instrument can be accepted as a clinical tool. It is probable that a combination of
several methods will be needed for PD. The cardinal motor symptoms of PD
only emerge after the degeneration of about 60-80% of the dopaminergic
neurons; thus patients get diagnosed at a very late disease stage. As the disease
progresses, the management of late-stage motor complications and non-motor
symptoms remains particularly challenging and will benefit from further clinical
research. To fully understand the etiology and mechanisms involved in the
pathogenesis of PD, valid model systems are needed.
INTRODUCTION: Parkinson’s disease (PD) was Many spontaneous movements like arm swinging,
first described by Dr. James Parkinson in a book blinking, and swallowing is reduced or lost. Tremor
entitled “An Essay on the Shaking Palsy,” will be maximal when the limb is at rest and
published in 1817 1. It is sometimes called reduced with voluntary movement. Later during the
idiopathic Parkinsonism but usually referred to as disease, there is a notorious failure in postural
Parkinson’s disease, to honor the physician who reflexes, impaired balance and general instability 3.
first described it. The clinical characteristics of PD Non-motor symptoms of PD include autonomic
are bradykinesia, akinesias or no movement, dysfunctions, apathy, depressions, sleep disorders,
rigidity and tremor 2. fatigue, pain and dementia 4. Epidemiological
QUICK RESPONSE CODE studies suggest that environmental factors may play
DOI:
10.13040/IJPSR.0975-8232.10(6).2654-62 an important role in most sporadic cases of the
disease where no apparent genetic linkage was
The article can be accessed online on
established 5. About 1% of the population above
www.ijpsr.com 60 years is affected by Parkinson’s disease 6.
Several reports are in accord that the occurrence of
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.10(6).2654-62 PD is more common in men than women, which

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may be linked to the potential neuroprotective In Fig. 1, the degeneration of dopaminergic

properties of estrogen demonstrated both in-vitro neurons result in the increased inhibition of the
and in-vivo 7. Parkinsonian symptoms are more globus pallidus external; thus the output of globus
predominant in premenopausal, and they are pallidus internal is inhibitory. However, this
reported to require more L-DOPA during inhibitory output causes the excitation of the
menstruation when estrogen levels are reduced 8. subthalamic nucleus. The main reason behind the
Moreover, cognitive functions were found to be occurrence of Parkinsonism is the increased
improved in postmenopausal women who inhibition of the thalamus. Finally, reduced
underwent Oestrogen replacement, the latter which excitation of the motor cortex results in the
may delay the development of cognitive occurrence of rigidity, bradykinesia, and the other
impairments and dementia in PD 9. PD symptoms 16.
According to the studies conducted in America,
Parkinson’s disease is more prevalent in
Caucasians than in African Americans, thus
signifying that Caucasians are genetically more
susceptible 10. According to the studies conducted
in Asia, Parkinson’s disease is found to be more
prevalent among the Parsi community in India, thus
signifying a major genetic role in disease causation
11
. Incidences of PD are more common in the rural
population. Exposure to pesticides used in
agricultural practices is the main reason behind the FIG. 1: THE EXCITATORY (GREEN) AND INHIBITORY
prevalence of PD in rural areas 12. (RED) OUTFLOW OF THE BASAL GANGLIA
MEDIATED BY DOPAMINE
Pathophysiology of Parkinson’s disease:
Parkinson's disease (PD) is characterized by an LBs are a pathological hallmark of sporadic and
imbalance between acetylcholine and dopamine 13. some familial forms of PD and indicate the
PD involves the degeneration of dopaminergic involvement of protein mishandling in disease
neurons in the substantia nigra pars compacta pathogenesis. The presence of Lewy bodies are
(SNpc), which results in the depletion of striatal reported to contribute to the manifestation of
dopamine 14. This neurotransmitter regulates the dementia in PD, but the pathology related to mild
excitatory and inhibitory outflow of the basal cognitive impairments in PD is less known, mainly
ganglia 15. because patients usually survive until these
symptoms develop into dementia 18. The Lewy
The basal ganglia are a selection of nuclei that play body density was found to be five times greater in
a key role in the control of body movements. The postmortem brain samples from PD patients with
first coherent model of the basal ganglia circuitry dementia as compared with non-demented patients
was developed starting in the middle of the 80s and with PD 19, 20.
described how the basal ganglia integrated
information from different brain regions and In PD patients, Lewy bodies are more predominant
generated feedback signals to the cerebral cortex 16. in the limbic structures, cholinergic forebrain
neurons, the cerebral cortex, and in the brainstem
In existing neuro-anatomy, the striatum (putamen nuclei, like the noradrenergic locus coeruleus and
and caudate nucleus), the pallidus (internal and the serotonergic raphe nuclei 21. Presence of α-
external), the subthalamic nucleus and the Synuclein is one of a prominent feature of Lewy
substantia nigra (pars compacta and reticulata) are bodies in idiopathic PD. α-Synuclein is normally a
considered the nuclei of the basal ganglia. It has soluble unfolded protein, but it can aggregate into
been demonstrated that the nuclei as mentioned insoluble amyloid fibrils which then may form
earlier play a key role in mediating motor and non- Lewy bodies, followed by subsequent ubiquity-
motor behavior, cognition and emotion 17. nation and accumulation of neurofilaments 22.

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32
At high concentrations, α-Synuclein protein self- . PARKIN is involved in maintaining normal UPS
aggregate in the cytoplasm to form Lewy-body-like function; disease-linked mutations in these genes
fibrils and discrete spherical assemblies, and this would lead to a similar set of events precipitating in
process is accelerated in the mutant forms of α- the demise of DA neurons. Structural and
synuclein 23. α-Synuclein species may be associated functional deficits in the 20/26S proteasome in the
with UPS dysfunction through binding and SNpc of sporadic PD patients are observed. Failure
inhibiting the 20/26S proteasome, and mutated or of UPS results into the accumulation of toxic
aggregated forms of α-synuclein may also misfolded proteins, which further degrade the
overwhelm the degradative capacity of the degradative capacity of the proteasome and may
proteasome, leading to further impairment 24, 25, 26. lead to further impairment 26.

Etiology of Parkinson’s Disease: DJ 1 Gene Mutation: DJ 1 is a molecular

Genetic Mutations: Several gene mutations have chaperone with roles in antioxidant gene expression
been described in patients with a familial form of and possibly counter oxidative stress in
the disease e.g., SNPCA gene mutation, Leucine- mitochondria. DJ-1 does not appear to be localized
rich repeat kinase 2 gene (LRRK2) mutation, to LBs in sporadic PD and other synucleinopathies
UCLH gene mutation, DJ 1 gene mutation, PINK1 but does co-localize with tau-positive inclusions in
gene mutation resulting in PD 27. some neurodegenerative tauopathies and with α-
synuclein-positive glial inclusions in multiple
SNPCA Gene Mutation: SNPCA gene mutation system atrophy 33, 27, which suggests that DJ-1 may
causes an overabundance of α-synuclein, which play a diverse role in seemingly distinct
may cause mitochondrial dysfunction and neuronal neurodegenerative diseases. Furthermore, insoluble
death. Damaged mitochondria promote α-synuclein forms of DJ-1 are dramatically increased in the
production. α- Synuclein is a highly charged 140- brains of sporadic PD patients perhaps also
amino acid heat-stable protein that is soluble and implicating DJ-1 in sporadic forms of this disease
natively “unfolded” 28, 29. α-Synuclein species may 34
. The physiological function of DJ-1 is unclear,
be associated with UPS dysfunction through but evidence suggests that DJ-1 may function as an
binding and inhibiting the 20/26S proteasome, and anti-oxidant protein or as a sensor of oxidative
mutated or aggregated forms of α-synuclein may stress. For example, DJ-1 demonstrates an acidic
also overwhelm the degradative capacity of the shift in isoelectric point in cultured cells following
proteasome, leading to further impairment 24, 25, 26. oxidative stress owing mainly to oxidation of
The consistent presence of fibrillar α-synuclein as a cysteine residues, particularly Cys106, which can
major component of LBs in PD 30, and the be converted to a cysteine sulfinic acid (Cys-SO2H)
formation of LB-like inclusions containing α- 35, 36
. DJ-1 can also eliminate hydrogen peroxide in
synuclein following proteasome inhibition in-vivo vitro by oxidizing itself suggesting that it may
31
, support this notion. LBs are a pathological function, in part, as a direct scavenger of ROS 37.
hallmark of sporadic and some familial forms of
PD and indicate the involvement of protein In cultured cells, overexpression of DJ-1 protects
mishandling in disease pathogenesis, although we against oxidative injury whereas knockdown of DJ-
do not know whether LB formation is a primary or 1 by short interfering RNA enhances the
secondary event. The role of LB formation in PD is susceptibility to oxidative stress. DJ-1 is a
the subject of some controversy with both component of the UPS and may confer protection
pathogenic and protective mechanisms being by functioning as a molecular chaperone or
proposed 25. protease to refold or promote the degradation of
misfolded or aggregated proteins 37.
PARKIN Gene Mutation: PARKIN normally tags
protein with ubiquitin and plays a role in Oxidative Stress and Lipid-peroxidation: In
mitochondrial homeostasis. PARKIN gene Parkinson’s disease it is accepted that oxidative
mutation may cause impairment of the UPS and stress is critically involved in the dopaminergic
protein mishandling may also cause the molecular neuron death since the SN of PD patients exhibits
pathogenesis of familial and sporadic forms of PD increased levels of oxidized lipids, proteins and

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DNA and a decrease in the levels of glutathione cognitive decline in PD 43. Activated microglia
(GSH) 38. There is evidence of oxidative stress in produce a variety of inflammatory cytokines,
the brains of PD patients. Sufficient data is including interleukin (IL)-2. Furthermore, activated
available which indicates the presence of increased microglia can be phagocytic and release pro-
levels of malondialdehyde (MDA), and lipid inflammatory factors such as TNFα, prostaglandin
hydroperoxide, products of lipid peroxidation in the E2 (PGE2), INFγ, and ROS such as NO-, H2O2, and
substantial Niagra pars compacta (SNpc) region in O2−, which are all toxic to neurons 44. Furuya and
the brain of PD patient 39. Oxidative stress has colleagues reported that caspase-11, which is
received the most attention in PD because of the predominantly expressed in microglia in the SN,
potential of the oxidative metabolism of dopamine can produce cell death by regulating the expression
to yield hydrogen peroxide (H2O2) and other of cytotoxic cytokines. Caspase-11 null mice were
reactive oxygen species (ROS) 40. Oxidant stress resistant to the neurotoxic effects of an acute MPTP
and consequent cell death could develop in the treatment 45. However, inhibition of microglia
SNpc under circumstances in which there is (a) activation relieved the degeneration of DAergic
increased dopamine turnover, resulting in excess neurons 46, 47. Increased levels of inflammatory
peroxide formation; (b) a deficiency in glutathione cytokines have also been found in the nigrostriatal
(GSH), thereby diminishing the brain’s capacity to regions and cerebrospinal fluid (CSF) of patients
clear H2O2; or (c) an increase in reactive iron, with PD. Clinical studies have shown that IL-2
which can promote OH- formation. levels are increased in the caudate nucleus and the
CSF of the patients with PD 48. Since DAergic
Indeed, postmortem studies in PD brains neurons are more vulnerable to inflammatory
demonstrate increased iron, decreased GSH, and cytokines, these cytokines have been implicated in
oxidative damage to lipids, proteins, and DNA, cognitive impairment in PD 43.
suggesting that the SNpc is in a state of oxidant
stress 41. Most attention has been directed to the Mitochondrial Dysfunctioning: Mutations in five
finding of a selective decrease in the reduced form genes encoding α-synuclein, parkin, UCH-L1,
of glutathione (GSH) in the SNpc in PD 42. A PINK1, and DJ-1 are associated with familial forms
reduction in GSH may impair H2O2 clearance and of PD through pathogenic pathways that may
promote OH- formation, particularly in the commonly lead to deficits in mitochondrial and
presence of increased iron. The cause of the UPS function. PINK1, parkin, and DJ-1 may play a
decrease in GSH in PD is unknown. The major role in normal mitochondrial function, whereas
enzymes linked with glutathione synthesis remain parkin, UCH-L1, and DJ-1 may be involved in
unaffected. There is, however, a significant normal UPS function. α-Synuclein fibrillation and
increase in the level of gamma-glutamyl aggregation are promoted by pathogenic mutations,
transpeptidase, the enzyme responsible for the oxidative stress, and oxidation of cytosolic
translocation of glutathione precursors and dopamine (DA), leading to impaired UPS function
metabolism of the oxidized form of glutathione and possibly mitochondrial damage. α-Synuclein
(GSSG) 44. Increased ϒ-GTT helps to survive cells may normally be degraded by the UPS 49. Some
to recruit glutathione precursors into the cell to environmental toxins can inhibit complex-I and
replenish diminished levels of GSH or a lead to mitochondrial dysfunction 50, 51. Impaired
compensatory mechanism to remove potentially mitochondrial function leads to oxidative stress,
toxic GSSG formed as a consequence of oxidant deficits in ATP synthesis, and α-synuclein
stress 39. aggregation, which may contribute to UPS
dysfunction 52.
Inflammation: Inflammation has also been
proposed as a possible mechanism in the Impairment of the Ubiquitin-Proteasome
pathogenesis of PD. Activated microglia have been System: Impairment of the UPS and protein
observed in the substantia nigra, putamen, where mishandling may also cause the molecular
DA loss is prominent, and also in the hippocampus pathogenesis of familial and sporadic forms of PD
32
of patients with PD, which has been suggested to . PARKIN, UCH-L1, and DJ-1 may be involved
be responsible for neuronal dysfunction and in maintaining normal UPS function; disease-

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linked mutations in these genes would lead to a dopaminergic system; they are not successful
similar set of events precipitating in the demise of enough to study the progressive nature of PD 57.
DA neurons. Structural and functional deficits in Below is a brief overview of major experimental
the 20/26S proteasome in the SNpc of sporadic PD models of PD.
patients are observed. Failure of UPS results into
the accumulation of misfolded proteins, which Mouse models using 1-methyl-4-phenyl-1,2,3,6-
further degrade the degradative capacity of the tetrahydropyridine (MPTP) are among the most
proteasome and thus leading to further impairment widely used. MPTP mouse models have shed light
in PD 26. on the pathophysiology as well as some of the
causes of the disease. MPTP model has provided
Exposure to Manganese and Other investigators with a reliable and valid model for
Catecholamine-Depleting Agents: Manganese is studying symptomatic relief and neuroprotective
an essential trace mineral necessary for normal effect of drugs. MPTP resembles some known
development and biological function 53. Excessive environmental compounds, including herbicides
exposure to manganese is a well-recognized such as paraquat 58 and the garden insecticide/fish
occupational and environmental hazard, which can toxin, rotenone 59; both have been shown to induce
lead to an extrapyramidal syndrome, referred to as degeneration of dopaminergic neurons 60, 61. The
manganism 54. Although this condition has motor neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
symptoms that resemble PD, it also has several pyridine (MPTP) results in a clinical syndrome
characteristics features different from PD, such as closely resembling Parkinson’s disease (PD) in
dystonia and the lack of response to dopamine both man and primates. MPTP is a meperidine
replacement therapy 14. Catecholamine-depleting analog which is metabolized to 1-methyl-4-
agents like Reserpine and Alpha-methyl-para- phenylpyridinium (MPP+) by the enzyme
tyrosine (AMPT) are known to induce monoamine oxidase B (MAO-B).
Parkinsonism. The first animal model for PD was
demonstrated by Carlsson in the 1950s using MPTP has been shown to accumulate within the
rabbits treated with reserpine. Reserpine is a mitochondria as MPP+ 62, which, through its
catecholamine-depleting agent that blocks vesicular interaction with complex I of mitochondrial
storage of monoamines. Alpha-methyl-para- oxidative phosphorylation, causes a reduction in
tyrosine (AMPT), like reserpine, serves as an mouse striatal and midbrain ATP levels. This
effective catecholamine-depleting agent. By reduction in conjunction with the increased
directly inhibiting tyrosine hydroxylase (the rate- generation of reactive oxygen species most likely
limiting enzyme in dopamine biosynthesis), the results in the ultrastructural abnormalities that
nascent synthesis of dopamine in neurons of the befall mitochondria and the rest of the cell. The
substantia nigra pars compacta and the ventral major advantage of this model is that the behavioral
tegmental area is prevented 55. syndrome closely bears a resemblance to the
clinical features of idiopathic PD 63, 64, 65.
Experimental Models of Parkinson’s Disease:
Valid animal models that mimic the progressive The first toxin-induced animal model of PD to be
disease state of PD are essential tools to better generated was the 6-OHDA model 66. 6-OHDA
understand the early pathogenesis of PD. Exposure model involves the unilateral ablation of the
to certain neurotoxins like 1-Methyl-4-Phenyl- dopaminergic neurons, which project from the
1,2,3,6-Tetrahydropyridine (MPTP), 6-Hydroxy- SNpc to the striatum. 6-OHDA is a hydroxylated
dopamine (6-OHDA), Rotenone and Paraquat can analogue of dopamine with a high affinity for
induce Parkinson’s disease. These neurotoxins are DAT, which does not cross the blood-brain barrier
known to produce the key features of PD like and thus must be locally injected into the brain.
certain motor defects, progressive loss of After entering into the cell through DAT-mediated
dopaminergic neurons in substantia nigra pars transportation, 6-OHDA tends to accumulates in
compacta (SNpc), and the formation of Lewy mitochondria where it inhibits complex I. 6-OHDA
bodies 56. Since 6-OHDA and MPTP models are can also auto-oxidate, resulting in the production of
known to induce an acute ablation of the hydrogen peroxide (H2O2) 67.

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6-OHDA is directly injected into the SNpc or into cycling to produce the free radical superoxide, thus
the medial forebrain bundle (MFB), which harbors inducing oxidative stress-mediated neurotoxicity 74.
the projections of the A9 dopaminergic cells that The toxicity of this herbicide is mediated through
originates in the SNpc and end in the striatum. the formation of monocationic radical by NADPH:
Dopaminergic neurons start to degenerate 12 h cytochrome P-450 reductase and NADH:
after the 6-OHDA injection, and after 2-3 days ubiquinone oxidoreductase reduction of paraquat.
there is a marked loss of dopaminergic terminals in In comparison to MPP+ and rotenone, the affinity
the striatum is observed which is accompanied by of paraquat complex is much low, therefore
dopamine depletion and leads to 90-100% loss of complex do not appear to be part of its neurotoxic
dopaminergic neurons 67. It is common to perform mechanism 73.
SNpc/MFB 6-OHDA lesions unilaterally, leaving
one hemisphere intact, which increases the viability CONCLUSION: Unfortunately, our understanding
of the animals and provides a useful model system of the critical molecular events causing neuro-
to study and quantify L-DOPA-induced dyskinesias degeneration in PD is limited, and consequently
and stereotypes 68. Unilaterally lesioned animals there is little progress in the pharmacotherapy of
display a characteristic rotational behavior when PD, especially to interfere with the disease
challenged with drugs that stimulate striatal progression. The genuine complexity of PD as a
dopamine receptors directly or indirectly, such as syndrome with multiple aetiologies should be kept
apomorphine, L-DOPA and amphetamine 69. In in the spotlight to ensure progress in the field.
another 6-OHDA-induced model the injections are Thus, it seems logical to stress the importance of
made into the striatum, often bilaterally, resulting the ability to diagnose potential Parkinsonian
in a comparatively milder and progressive loss of patients accurately.
dopaminergic neurons over 4-6 weeks post-
Many simulated animal models of PD have been
injection 70.
developed to understand the pathogenesis and test
Rotenone is a naturally occurring, a highly potential therapeutics of this disease. Such
lipophilic cytotoxic pesticide. Rotenone exposure is simulated models are useful to screen drugs for
known to produce certain hallmark features of PD symptomatic treatment of the disease, besides these
which include nigrostriatal dopaminergic models, transgenic and knockout models are useful
degeneration and formation of alpha-synuclein for evaluating the role of genetics in PD. With
filamentous inclusions in brain samples of PD using the model of toxins, it is possible to develop
patients. Chronic exposure to pesticides is a known a progressive model by tempering the toxic doses.
risk factor of PD, which has led to numerous
Future scope of the study involves improvement in
studies on agricultural pesticides and neuro-
the screening and the evaluation of Anti-
degeneration, and to the discoveries of additional
Parkinsonian drugs and developmental processes.
toxin-induced animal models of PD. Chronic
The above-mentioned animal models can prove to
systemic injections of the pesticide rotenone induce
be helpful in understanding mechanisms for the
Parkinsonism in rats by entering dopaminergic
death of dopaminergic neurons. Hence, it is
neurons in a DAT-independent manner and
necessary to investigate these animal models to
inhibiting mitochondrial complex I 71. Inhibition of
understand the involvement of mitochondrial
complex I lead to the formation of ROS, and
dysfunction, energy (ATP) depletion, free-radicals
subsequently to selective nigrostriatal
72 production, apoptosis, and glutamate excitotoxicity
dopaminergic degeneration .
in the pathogenesis of PD.
The herbicide paraquat, which is structurally
ACKNOWLEDGEMENT: The author was deep
similar to MPP+, is also used as a systemic model
sense of gratitude to Hygia Institute of
of PD. In contrast to MPTP and rotenone, paraquat
Pharmaceutical Education and Research (HIPER),
is incapable of crossing the blood-brain barrier.
for their continuous support and inspiration.
Paraquat is known to enter the brain via amino acid
transporters 73, and dopaminergic neurons via DAT CONFLICT OF INTEREST: Nil
74
. Within the neuron paraquat go through redox

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How to cite this article:

Singh R and Srivastava A: Parkinsonism: a general motor disability. Int J Pharm Sci & Res 2019; 10(6): 2654-62. doi: 10.13040/IJPSR.
0975-8232.10(6).2654-62.
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