Melinda Fitzgerald

Curtin University, Perth, Curtin Health Innovation Research Institute, Faculty Member

The University of Western Australia, Experimental and Regenerative Neurosciences, Faculty Member

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Melinda Fitzgerald is Professor of Neurotrauma and the Leader of the national Mission for Traumatic Brain Injury, an MRFF initiative providing $50 million in funding over 10 years. She is Deputy Director of the Curtin Health Innovation Research Institute, Curtin University, jointly appointed by the Perron Institute for Neurological and Translational Science, and located at the new Sarich Neuroscience Research Institute.
http://orcid.org/0000-0002-4823-8179
Prof Fitzgerald has 15 years post-doctoral experience (note parental career disruption 1998-2005) and leads a team of 12 researchers and post-graduate students in research focused around understanding and preventing the loss of function that occurs following neurotrauma. She uses innovative techniques to understand changes to key biochemical, cellular and structural components of nerves following injury and assesses treatment strategies including nanotechnologies and combinatorial pharmacotherapeutics. She conducts collaborative clinical trials designed to predict outcomes following mild traumatic brain injury, leading towards early intervention treatment strategies.
Scientific contributions
In her 15 post-doctoral years Prof Fitzgerald has published 82 papers (50 since 2013), of which she is last author on the majority. Recent papers have been published in influential, international journals, including discipline leading J Neuroscience, Nature Nano (IF=38.98), ACS Nano (IF=10.5), Biomaterials (IF=8.4), Small (IF=7.8), IOVS, Scientific Reports, Neuropharmacology and J Neurotrauma. She has been invited to speak at numerous local, national and international conferences, including keynote and Symposium presentations. Currently Held Grants/Projects total $1.5 million; she is CIA for all of these; total funding awarded for her career is $8.4 million, $5.3 million as CIA. Prof Fitzgerald currently holds a CIA Project Grant and has previously held an NMHRC Career Development Fellowship and three NHMRC Project grants as CIA. A patent entitled ‘Multifunctional Nanoparticles’ reached international PCT stage and was developed by a biotechnology company. In the past 5 years Prof Fitzgerald has supervised 25 Honours students or equivalent, 14 PhD students (7 completions), 6 post-doctoral researchers and gives guest lectures.

Contribution to discipline
Prof Fitzgerald’s commitment to discipline is evidenced by her roles as Leader Mission for Traumatic Brain Injury; Chair formative team for Vision for TBI (currently Impact-TBI); Deputy Director Curtin Health Innovation Research Institute; Research representative on Project Steering Group, WA State Plan for Neuroscience; Perron Institute Representative for Neurosciences Victoria; Chairperson and Convener of the annual Symposium of Western Australian Neuroscience (SWAN), and the Bryant Stokes Neuroscience Seminar Series. She coordinates dissemination of collated information regarding all seminars in science and health in Perth. Prof Fitzgerald is a Handling Editor for the Journal of Neurochemistry, the Australian representative for the Asia Pacific Regional Committee for IBRO, and an Editorial Board Member for Neural Regeneration Research. She serves on NHMRC and MS Australia Grant Review Panels; the Scientific Advisory Committee of the Australian Alzheimer’s Research Foundation and the Raine Foundation Clinician Research Fellowship (CRF) Advisory Panel; reviews for numerous scientific journals including EJN, IOVS, Neurochem. Int., and international funding bodies including fight for Sight UK, MS Australia and the Alzheimer’s Australia Dementia Research Foundation. In addition, Prof Fitzgerald participated in Homeward Bound 2016, an international leadership and strategy program for women scientists, run as an expedition to Antarctica, designed to increase the proportion of women in the higher levels of science. As a consequence Prof Fitzgerald instituted a Faculty gender equity group, coordinates the STEAM mentoring program for PhD students and early career researchers, and is a member of the Australasian Neuroscience Society Gender Equity and Diversity Committee. Prof Fitzgerald Chairs the ARC Centre for Integrative Brain Function Gender Equity and Diversity Committee and is a member of the Perkins Institute EMCR Mentoring Committee. She regularly speaks at institutional, scientific and community events regarding gender equity in science and co-founded the Australasian Women in Neuroscience Facebook page.
Address: Sarich Neuroscience Research Institute Building
8 Verdun St, Nedlands 6009 WA
Australia

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Papers by Melinda Fitzgerald

Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma

by Charis Szymanski and Melinda Fitzgerald

Neuropharmacology, 2013

Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with ... more Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca 2þ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca 2þ channels has shown promise in preclinical studies, but clinical trials have been disappointing and combinatorial approaches are needed. We assessed efficacy of multiple combinations of three Ca 2þ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca 2þ channels; oxidised adenosinetriphosphate (oxATP) to inhibit purinergic P2X 7 receptors and/or 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid (INQ) to inhibit Ca 2þ permeable a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca 2þ channel inhibitors delivered in combination significantly preserved visual function, as assessed using the optokinetic nystagmus visual reflex, at 3 months after injury. Preservation of retinal ganglion cells was partial and is unlikely to have accounted for differential effects on function. A range of the Ca 2þ channel inhibitor combinations prevented swelling of optic nerve vulnerable to secondary degeneration. Each of the treatments involving lomerizine significantly increased the proportion of axons with normal compact myelin. Nevertheless, limiting decompaction of myelin was not sufficient for preservation of function in our model. Multiple combinations of Ca 2þ channel inhibitors reduced formation of atypical node/paranode complexes; outcomes were not associated with preservation of visual function. However, prevention of lengthening of the paranodal gap that was only achieved by treatment with the three Ca 2þ channel inhibitors in combination was an important additional effect that likely contributed to the associated preservation of the optokinetic reflex using this combinatorial treatment strategy.

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The effects of concentration-dependent morphology of self-assembling RADA16 nanoscaffolds on mixed retinal cultures

by Carole Bartlett, Dominic Ho, and Melinda Fitzgerald

Nanoscale, 2011

RADA16 self-assembling peptide nanofiber scaffolds (SAPNSs) have been shown to have positive effe... more RADA16 self-assembling peptide nanofiber scaffolds (SAPNSs) have been shown to have positive effects on neural regeneration following injury to the central nervous system in vivo, but mechanisms are unclear. Here we show that RADA16 SAPNSs form scaffolds of increasing fiber density with increasing peptide concentration which in turn has a concentration-dependent effect on neurons and astrocytes in mixed retinal cultures. Importantly, we report that the final nanoscale fiber architecture is an important factor to consider in designing scaffolds to promote regeneration in the central nervous system.

Early in vivo changes in calcium ions, oxidative stress markers, and ion channel immunoreactivity following partial injury to the optic nerve

by Carole Bartlett and Melinda Fitzgerald

Journal of Neuroscience Research, 2012

CNS injury is often localized but can be followed by more widespread secondary degenerative event... more CNS injury is often localized but can be followed by more widespread secondary degenerative events that usually result in greater functional loss. Using a partial transection model in rat optic nerve (ON). we recently demonstrated in vivo increases in the oxidative stress-associated enzyme MnSOD 5 min after injury. However, mechanisms by which early oxidative stress spreads remain unclear. In the present study, we assessed ion distributions, additional oxidative stress indicators, and ion channel immunoreactivity in ON in the first 24 hr after partial transection. Using nanoscale secondary ion mass spectroscopy (NanoSIMS), we demonstrate changes in the distribution pattern of Ca ions following partial ON transection. Regions of elevated Ca ions in normal ON in vivo rapidly decrease following partial ON transection, but there is an increasingly punctate distribution at 5 min and 24 hr after injury. We also show rapid decreases in catalase activity and later increases in immunoreactivity of the advanced glycation end product carboxymethyl lysine in astrocytes. Increased oxidative stress in astrocytes is accompanied by significantly increased immunoreactivity of the AMPA receptor subunit GluR1 and aquaporin 4 (AQP4). Taken together, the results indicate that Ca ion changes and oxidative stress are early events following partial ON injury that are associated with changes in GluR1 AMPA receptor subunits and altered ionic balance resulting from increased AQP4.

Number of Tunel+ cells, 8OHDG and GFAP immunoreactivity following pre-treatment with 670 nm or 830 nm R/NIR-IT or sham treatment and light induced retinal degeneration, compared to uninjured animals

by Carole Bartlett and Melinda Fitzgerald

Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma

by Carole Bartlett, Charis Szymanski, and Melinda Fitzgerald

Neuropharmacology, 2013

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Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment

by Carole Bartlett and Melinda Fitzgerald

PLoS ONE, 2013

Secondary degeneration of nerve tissue adjacent to a traumatic injury results in further loss of ... more Secondary degeneration of nerve tissue adjacent to a traumatic injury results in further loss of neurons, glia and function, via mechanisms that may involve oxidative stress. However, changes in indicators of oxidative stress have not yet been demonstrated in oligodendrocytes vulnerable to secondary degeneration in vivo. We show increases in the oxidative stress indicator carboxymethyl lysine at days 1 and 3 after injury in oligodendrocytes vulnerable to secondary degeneration. Dihydroethidium staining for superoxide is reduced, indicating endogenous control of this particular reactive species after injury. Concurrently, node of Ranvier/paranode complexes are altered, with significant lengthening of the paranodal gap and paranode as well as paranode disorganisation. Therapeutic administration of 670 nm light is thought to improve oxidative metabolism via mechanisms that may include increased activity of cytochrome c oxidase. Here, we show that light at 670 nm, delivered for 30 minutes per day, results in in vivo increases in cytochrome c oxidase activity co-localised with oligodendrocytes. Short term (1 day) 670 nm light treatment is associated with reductions in reactive species at the injury site. In optic nerve vulnerable to secondary degeneration superoxide in oligodendrocytes is reduced relative to handling controls, and is associated with reduced paranode abnormalities. Long term (3 month) administration of 670 nm light preserves retinal ganglion cells vulnerable to secondary degeneration and maintains visual function, as assessed by the optokinetic nystagmus visual reflex. Light at a wavelength of 670 nm may serve as a therapeutic intervention for treatment of secondary degeneration following neurotrauma. Citation: Szymanski CR, Chiha W, Morellini N, Cummins N, Bartlett CA, et al. (2013) Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment. PLoS ONE 8(6): e66448.

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Metallothionein-IIA promotes neurite growth via the megalin receptor

by Carole Bartlett, Pia Nairn, Adrian West, and Melinda Fitzgerald

Experimental Brain Research, 2007

Metallothionein (MT)-I/II has been shown to be neuroprotective and neuroregenerative in a model o... more Metallothionein (MT)-I/II has been shown to be neuroprotective and neuroregenerative in a model of rat cortical brain injury. Here we examine expression patterns of MT-I/II and its putative receptor megalin in rat retina. At neonatal stages, MT-I/II was present in retinal ganglion cells (RGCs) but not glial or amacrine cells; megalin was present throughout the retina. Whilst MT-I/II was absent from adult RGC in normal animals and after optic nerve transection, the constitutive megalin expression in RGCs was lost following optic nerve transection. In vitro MT-IIA treatment stimulated neuritic growth: more RGCs grew neurites longer than 25 m (P < 0.05) in dissociated retinal cultures and neurite extension increased in retinal explants (P < 0.05). MT-IIA treatment of mixed retinal cultures increased megalin expression in RGCs, and pre-treating cells with anti-megalin antibodies prevented MT-IIA-stimulated neurite extension. Our results indicate that MT-IIA stimulates neurite outgrowth in RGCs and may do so via the megalin receptor; we propose that neurite extension is triggered via signal transduction pathways activated by the NPxY motifs of megalin's cytoplasmic tail.

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In vivo Imaging and Biodistribution of Multimodal Polymeric Nanoparticles Delivered to the Optic Nerve

by Carole Bartlett and Melinda Fitzgerald

Small, 2012

The use of nanoparticles for targeted delivery of therapeutic agents to sites of injury or diseas... more The use of nanoparticles for targeted delivery of therapeutic agents to sites of injury or disease in the central nervous system (CNS) holds great promise. However, the biodistribution of nanoparticles following in vivo administration is often unknown, and concerns have been raised regarding potential toxicity. Using poly(glycidyl methacrylate) (PGMA) nanoparticles coated with polyethylenimine (PEI) and containing superparamagnetic iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent and rhodamine B as a fluorophore, whole animal MRI and fluorescence analyses are used to demonstrate that these nanoparticles (NP) remain close to the site of injection into a partial injury of the optic nerve, a CNS white matter tract. In addition, some of these NP enter axons and are transported to parent neuronal somata. NP also remain in the eye following intravitreal injection, a non-injury model. Considerable infiltration of activated microglia/macrophages occurs in both models. Using magnetic concentration and fluorescence visualization of tissue homogenates, no dissemination of the NP into peripheral tissues is observed. Histopathological analysis reveals no toxicity in organs other than at the injection sites. Multifunctional nanoparticles may be a useful mechanism to deliver therapeutic agents to the injury site and somata of injured CNS neurons and thus may be of therapeutic value following brain or spinal cord trauma.

Comparative assessment of phototherapy protocols for reduction of oxidative stress in partially transected spinal cord slices undergoing secondary degeneration

by Carole Bartlett and Melinda Fitzgerald

BMC Neuroscience, 2016

Red/near-infrared light therapy (R/NIR-LT) has been developed as a treatment for a range of condi... more Red/near-infrared light therapy (R/NIR-LT) has been developed as a treatment for a range of conditions, including injury to the central nervous system (CNS). However, clinical trials have reported variable or sub-optimal outcomes, possibly because there are few optimized treatment protocols for the different target tissues. Moreover, the low absolute, and wavelength dependent, transmission of light by tissues overlying the target site make accurate dosing problematic. In order to optimize light therapy treatment parameters, we adapted a mouse spinal cord organotypic culture model to the rat, and characterized myelination and oxidative stress following a partial transection injury. The ex vivo model allows a more accurate assessment of the relative effect of different illumination wavelengths (adjusted for equal quantal intensity) on the target tissue. Using this model, we assessed oxidative stress following treatment with four different wavelengths of light: 450 nm (blue); 510 nm (green); 660 nm (red) or 860 nm (infrared) at three different intensities: 1.93 × 10(16) (low); 3.85 × 10(16) (intermediate) and 7.70 × 10(16) (high) photons/cm(2)/s. We demonstrate that the most effective of the tested wavelengths to reduce immunoreactivity of the oxidative stress indicator 3-nitrotyrosine (3NT) was 660 nm. 860 nm also provided beneficial effects at all tested intensities, significantly reducing oxidative stress levels relative to control (p ≤ 0.05). Our results indicate that R/NIR-LT is an effective antioxidant therapy, and indicate that effective wavelengths and ranges of intensities of treatment can be adapted for a variety of CNS injuries and conditions, depending upon the transmission properties of the tissue to be treated.

A Neurogenic Perspective of Sarcopenia: Time Course Study of Sciatic Nerves From Aging Mice

Journal of Neuropathology & Experimental Neurology, 2016

To elucidate the neural basis for age-related sarcopenia, we quantified morphologic and molecular... more To elucidate the neural basis for age-related sarcopenia, we quantified morphologic and molecular changes within sciatic nerves of aging male and female C57BL/6J mice aged between 3 and 27 months using immunoblotting, immunohistochemistry, and electron microscopy. Protein analyses by immunoblotting of nerves of male mice aged 4, 15, 18, 22, and 24 months showed increased levels of heavy chain SMI-32-positive neurofilaments, vimentin, tau5, choline acetyltransferase (ChAT), and p62 by 18-22 months. Similar protein increases were seen in 26-month-old compared with 3-month-old female mice. Immunostaining of longitudinal sections of old (27-month-old) male sciatic nerves revealed intense staining for tau5 and p62 that was increased compared with that at 3 months, but there were decreased numbers of axon profiles stained for ChAT or isolectin B4 (motor and sensory axons, respectively). Ultrastructural analysis revealed electron-dense aggregates within axons in peripheral nerves of old male mice; the proportion of axons that contained aggregates more than doubled between 15 and 27 months. Overall, the observed age-related accumulation of many proteins from about 18 months of age onward suggests impaired mechanisms for axonal transport and protein turnover. These peripheral nerve changes may contribute to the morphological and functional muscle deficits associated with sarcopenia.

Method for the Assessment of Effects of a Range of Wavelengths and Intensities of Red/near-infrared Light Therapy on Oxidative Stress <em>In Vitro</em>

Journal of Visualized Experiments, 2015

Red/near-infrared light therapy (R/NIR-LT), delivered by laser or light emitting diode (LED), imp... more Red/near-infrared light therapy (R/NIR-LT), delivered by laser or light emitting diode (LED), improves functional and morphological outcomes in a range of central nervous system injuries in vivo, possibly by reducing oxidative stress. However, effects of R/NIR-LT on oxidative stress have been shown to vary depending on wavelength or intensity of irradiation. Studies comparing treatment parameters are lacking, due to absence of commercially available devices that deliver multiple wavelengths or intensities, suitable for high through-put in vitro optimization studies. This protocol describes a technique for delivery of light at a range of wavelengths and intensities to optimize therapeutic doses required for a given injury model. We hypothesized that a method of delivering light, in which wavelength and intensity parameters could easily be altered, could facilitate determination of an optimal dose of R/NIR-LT for reducing reactive oxygen species (ROS) in vitro.

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Nanoparticle-mediated internalisation and release of a calcium channel blocker

Rsc Advances, 2012

ABSTRACT Lomerizine is a calcium channel blocker that selectively blocks L- and T-type Ca2+ chann... more ABSTRACT Lomerizine is a calcium channel blocker that selectively blocks L- and T-type Ca2+ channels, but it is effectively insoluble under physiological conditions. Herein we show that lomerizine can be released from a nanoparticle-based carrier by intracellular protonation in PC12 cells, suppressing Ca2+ influx in these cells in response to glutamate.

Characterization of polymeric nanoparticles for treatment of partial injury to the central nervous system

by Carole Bartlett and Melinda Fitzgerald

Data in Brief, 2016

Redefining the Role of Metallothionein within the Injured Brain: EXTRACELLULAR METALLOTHIONEINS PLAY AN IMPORTANT ROLE IN THE ASTROCYTE-NEURON RESPONSE TO INJURY

by Carole Bartlett and Melinda Fitzgerald

Journal of Biological Chemistry, 2008

A number of intracellular proteins that are protective after brain injury are classically thought... more A number of intracellular proteins that are protective after brain injury are classically thought to exert their effect within the expressing cell. The astrocytic metallothioneins (MT) are one example and are thought to act via intracellular free radical scavenging and heavy metal regulation, and in particular zinc. Indeed, we have previously established that astrocytic MTs are required for successful brain healing. Here we provide evidence for a fundamentally different mode of action relying upon intercellular transfer from astrocytes to neurons, which in turn leads to uptake-dependent axonal regeneration. First, we show that MT can be detected within the extracellular fluid of the injured brain, and that cultured astrocytes are capable of actively secreting MT in a regulatable manner. Second, we identify a receptor, megalin, that mediates MT transport into neurons. Third, we directly demonstrate for the first time the transfer of MT from astrocytes to neurons over a specific time course in vitro. Finally, we show that MT is rapidly internalized via the cell bodies of retinal ganglion cells in vivo and is a powerful promoter of axonal regeneration through the inhibitory environment of the completely severed mature optic nerve. Our work suggests that the protective functions of MT in the central nervous system should be widened from a purely astrocytic focus to include extracellular and intra-neuronal roles. This unsuspected action of MT represents a novel paradigm of astrocyte-neuronal interaction after injury and may have implications for the development of MT-based therapeutic agents.

An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles

by Carole Bartlett, Diwei Ho, Ivana Gachulincova, and Melinda Fitzgerald

Scientific reports, 2016

The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining... more The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable.

Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment

by Natalie Morellini and Melinda Fitzgerald

PLoS ONE, 2013

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Fab fragments from the monoclonal antibody ML3O bind to treated human myeloid leukemia cells

Traditionally, heat-shock proteins were believed to be located intracellularly; however, recent s... more Traditionally, heat-shock proteins were believed to be located intracellularly; however, recent studies have demonstrated that under certain circum- stances these proteins can be located at the cell surface. Murine ascites developed from the anti-mycobacterial hsp65 hybridoma ML3O have been shown to contain an antibody that binds to the surface of a range of stimulated myelomonocytic cell lines; however, as the

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Suppressing regrowth of microfluidic generated drug nanocrystals using polyelectrolyte coatings

RSC Advances

Crystalline meloxicam nanoparticles <100 nm in diameter are accessible using a microfluidic pl... more Crystalline meloxicam nanoparticles <100 nm in diameter are accessible using a microfluidic platform without the use of organic solvents, with a subsequent layer-by-layer polyelectrolyte encapsulation being effective in suppressing growth of macrocrystals, and imparting high colloidal stability for sustained release over 6-8 h with a t1/2ca.180 min.

Novel combinations of ion channel inhibitors for treatment of neurotrauma

Discovery medicine

Neurotrauma results in the progressive degeneration of neurons and glia surrounding the initial i... more Neurotrauma results in the progressive degeneration of neurons and glia surrounding the initial injury. Disruptions to myelin structure are a feature of these injuries and are thought to be triggered by excess calcium (Ca2+) influx into myelinating oligodendrocytes and/or their precursor cells. Calcium ions enter oligodendrocytes through a range of receptors including voltage gated calcium channels, N-methyl-D-aspartate (NMDA) receptors, Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and purinergic P2X7 receptors. Inhibitors have been used to limit excess Ca2+ entry following neurotrauma, but clinical success has been limited. We propose that combinations of calcium channel inhibitors may provide an alternative treatment strategy, whereby entry of excess Ca2+ flux through multiple routes is inhibited simultaneously.

Novel combinations of ion channel inhibitors for treatment of neurotrauma

Discovery medicine, 2015