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Title: Pharmacological and genetic modifications in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease
Author: Mounsey, Ross B.
ISNI:       0000 0004 2739 8872
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2013
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Parkinson’s disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain. Symptomatic therapies are available but no treatment slows or prevents the loss of neurons. To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients. Several processes have been implicated in its pathogenesis including sustained inflammation. Herein, the roles of potential regulators of immune response, the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs), are investigated. The ECS is composed of at least two receptors, their natural ligands and enzymes responsible for their breakdown. The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG), was added exogenously and its degradation inhibited to provide protection against MPTP-induced cell death. Furthermore, the addition of DFU, a selective inhibitor of inflammatory mediator cyclooxygnease-2 (COX-2), could increase these beneficial effects. Levels of 2-AG were upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits. Activation of the PPARs has previously been shown to be neuroprotective in several disease models. The neuroprotective effects of PPAR activation were investigated. Rosiglitazone, an agonist of the receptor, could not provide neuroprotection when levels of the receptor were diminished in vitro. Two PPAR isoforms, PPAR and PPAR, were subject to tissue-specific knock-out to elucidate their function in the regulation of inflammatory responses. Dual knock-out led to greater levels of MPTP-induced neuronal death, further supporting the importance of the PPARs in regulating inflammation and preventing cell death. The results expand the current understanding of the role that these two signalling systems have and their potential influence in PD.
Supervisor: Not available Sponsor: University of Aberdeen ; NHS Grampian Endowment Fund ; Parkinson's Disease Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Parkinson's disease