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Exploring the aetiology of pre-motor Parkinson's disease and the efficacy of potential neuroprotective therapies

Sancandi, Marco; (2021) Exploring the aetiology of pre-motor Parkinson's disease and the efficacy of potential neuroprotective therapies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The present thesis aimed at providing insight into the aetiology and treatment of Parkinson’s disease (PD), which symptomatology consists of both motor and non-motor symptoms (NMSs). The latter have been linked to a loss of neurotransmitters other than dopamine and they have been shown to be modulated by treatments that do not act directly on the dopaminergic system, such as the glucagon-like peptide-1 receptor agonist exendin-4 (EX-4). Nevertheless, the aetiology of NMs, alongside with their potential treatments, has yet to be fully investigated. In this study, through injections of the neurotoxins N-N-ethyl-2-bromobenzylamine (DSP-4) and 6-hydroxydopamine (6-OHDA), a rat model of early-stage PD was developed and validated. Animals displayed the NMS hyposmia and memory impairments in the absence of motor symptoms, suggesting the PD model is representative of an early stage of the disease. Next, the effect of partial noradrenergic and dopaminergic denervation in several brain regions within the olfactory pathway was investigated using immunohistochemical techniques. Surprisingly, the combined denervation led to a reduction in the expression of interneuronal calcium binding proteins (CBPs) in the primary olfactory cortex and prefrontal cortex, whilst the expression in the olfactory bulbs was found to be increased, alongside with dopaminergic expression. Additionally, GABAergic cells in CA2 of the PD model were found to be decreased compare with controls. Interestingly, the observed structural changes were partially prevented following treatment with EX-4. Additionally, two preliminary studies were conducted using the early-stage PD model to test two potential new treatments, a novel viral vector and probiotics, and their effectiveness in preventing neuronal loss in the Substantia Nigra. Overall, this rat model of early-stage PD offers a useful means for research into early diagnosis as well as early intervention of PD, possibly resulting in a delay of disease progression together with improved patient’s quality of life.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exploring the aetiology of pre-motor Parkinson's disease and the efficacy of potential neuroprotective therapies
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10132461
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