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Title: Role of inflammation in 6-hydroxydopamine model of Parkinson's disease and its modulation by Peroxisome Proliferator Activated Receptor gamma (PPAR-γ) agonist as a neuroprotective strategy
Author: Sadeghian, Mona
ISNI:       0000 0004 2686 8975
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Parkinson's disease is an age related progressive neurodegenerative disorder affecting ~2% of the population over the age of 65. The aetiology of Parkinson's disease is not fully understood and treatment limited. Hence, the goal of ongoing research is to understand and target the mechanisms underlying the disease process to halt or slow down its progression. Parkinson's disease is pathologically characterised by the loss of dopaminergic neurons in the substantial nigra that leads to the loss of innervation to the striatum, subsequently leading to the motor complications observed in Parkinson's sufferers. Recent clinical and experimental evidence suggests that inflammation, characterised by over activation of the brain's resident immune cells such as microglia/macrophages, play a detrimental role in Parkinson's pathology. This project, for the first time, aims to explore the time course of microglial activation in association with dopaminergic neuronal cell death in the substantia nigra utilising the 6-hydroxydopamine rat model of Parkinson's. The dynamics of morphological, immunophenotypic and phagocytic properties of activated microglia in the substantia nigra was assessed immunohistochemically. In addition we explored the cellular events between activated microglia and degenerating neurons in this model that had not been previously well defined. The role of matrix metalloproteinases as signalling molecules that activate microglia were also studied. Finally the significance of local microglial activation in the substantia nigra was elucidated by modulation of the microglial response via activation of the gamma subtype of peroxisome proliferator activated receptors. This project provided evidence that microglial activation preceded dopaminergic neuronal cell death in the substantia nigra and inhibition of microglial response serves as a neuroprotective strategy in Parkinson's disease.
Supervisor: Dexter, David Sponsor: GSK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral