Athauda, Dilan Sampath; (2018) Exenatide and the treatment of Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of people over the age of 65. Despite the best available medical and surgical therapies, there are no known treatments that can slow or alter clinical disease progression or continued neurodegeneration, thus any novel intervention that could delay or slow progression of PD would provide much needed health and socio-economic benefits. The mechanisms underlying PD pathogenesis remain unclear but there is accumulating evidence to suggesting that Type 2 diabetes and PD, both age-related diseases, share similar dysfunctional pathways. Alterations in metabolism, inflammation and mitochondrial function occur in both diseases and growing evidence suggests these pathways may impact on various tissues’ ability to respond to insulin, leading to “insulin resistance” in peripheral tissues and neurones, promoting cell death pathways and leading ultimately to diabetes and neurodegeneration respectively. The common pathways between these two conditions has led some to speculate that “insulin sensitizing” treatments for patients with Type 2 diabetes may be useful as novel treatments in neurodegenerative diseases such as PD. Exenatide is a Glucagon-like peptide-1 (GLP-1) agonist, currently licensed for the treatment for Type 2 diabetes and acts on insulin signalling pathways. It has demonstrated neuroprotective effects across a variety of animal toxin models of PD and also in a proof of concept, open label trial of mid-stage PD patients, conferring persistent motor and cognitive benefits sustained past the period of drug exposure. In this thesis I will present the first data from a fully randomised, placebo-controlled trial of exenatide in PD patients and explore the effects of exenatide on disease progression in PD and its influence on motor and non-motor symptoms. Furthermore, I will explore the pharmacokinetics of exenatide in this population and, utilising data from serum extracellular vesicles (exosomes) enriched for neuronal origin from the Exenatide-PD trial participants, demonstrate that peripherally administered exenatide can engage with neuronal insulin signalling pathways, providing some mechanistic context for the trial results. Taken together, data presented here will provide compelling evidence supporting the links between insulin signalling and PD and that the role of exenatide and other GLP-1 agonists as a novel treatment for PD should be explored further.

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