Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF) in a Novel Model of Parkinson's Disease
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Parkinson’s disease is a progressive neurodegenerative disorder, characterised histopathologically by the degenerating nigrostriatal pathway. Previous studies have shown a decrease in neurogenesis, dopaminergic neurons and neurotrophic factor levels in the Parkinson brain. This thesis investigates the capability of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) to stimulate endogenous neurogenesis and offer direct or indirect neuroprotection in a novel model of Parkinson’s disease. To assess the neurogenic capability of the postnatal substantia nigra, the effect of age and nigrostriatal circuitry function was examined. Animals were randomised into 2 cohorts; one cohort the control while the other received a partial unilateral 6-hydroxydopamine (6-OHDA; 4 μg) lesion. All animals received 10 day exposure to 5-ethynyl-2′-deoxyuridine (EdU; 25 mg/kg body weight) after lesion to label proliferative cells. An increase in age decreased neurogenic potential of the substantia nigra and dentate gyrus of rats. A partial lesion increased cell proliferation; with the change showing an interaction between age and treatment. The current data shows the highest neurogenic potential at day 28 after weaning, with a near complete lack of neurogenesis at 2 years. With increasing age, a decrease in neurotrophic factors has been reported. The current data supports the hypothesis for neurotrophic factors influencing endogenous neurogenesis. A novel Parkinson’s disease rat model that mimics human pathophysiology using a low dose rotenone induced intra-medial forebrain bundle lesion was developed. Rotenone is a highaffinity inhibitor of complex 1 of the mitochondrial electron transport chain. Complex 1 inhibition by rotenone causes the production of reactive oxygen species that result in oxidative damage of the dopaminergic neurons. The animal model demonstrated a glial response together with a slow degenerative change (cell stress; oxidative stress; α-synuclein production; cell death) similar to human Parkinson’s disease. This is a useful model for testing therapeutic interventions, including neuroprotective and neurogenic agents for Parkinson’s disease.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
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Published articles, and conference papers included in Appendices have not been published here.
Vascular endothelial growth factor (VEGF)
Platelet derived growth factor (PDGF)