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Title: Characterisation of metabotropic glutamate receptor 4 as a therapeutic target in Parkinson's disease
Author: Mann, Elizabeth Caroline
ISNI:       0000 0004 7660 330X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Parkinson's disease (PD) is a progressive, neurodegenerative disease with limited symptomatic treatment options and no currently licensed, disease-modifying therapies. This thesis sets out to examine the neuroprotective, therapeutic potential of systemically-administered compounds acting on metabotropic glutamate receptor 4 (mGluR4) in a rat 6-hydroxydopamine model of early-stage PD. Additionally, the rat model is explored for its ability to reflect the non-motor, in addition to motor, symptoms of PD. A positive allosteric modulator (PAM) and an agonist of mGluR4 were examined for their neuroprotective efficacy in the early stage model of PD. Although the PAM failed to provide neuroprotection, animals treated with the mGluR4 agonist show improved performance in motor tests and also significant protection of dopaminergic cells in the substantia nigra pars compacta. Furthermore, the mGluR4 agonist caused a significant reduction of motor disability without inducing any dyskinesia side-effects in a marmoset model of PD but failed to reduce existing dyskinesia. This mGluR4-mediated neuroprotection was hypothesised to arise from a number of different mechanisms including a reduction of excitotoxicity due to moderation of subthalamic nucleus (STN) overactivity (not explored here) and a reduction in inflammatory activity. The results presented here show that, although there may be some effect of systemic mGluR4 agonism on reducing inflammation, many other pathways may also be implicated as shown through a microarray highlighting gene expression significantly altered following agonist administration. In addition to studies on mGluR4, some model characterisation work was also carried out. Anxiety and craving, non-motor symptoms commonly seen in PD patients, were observed in the bilateral version of the early stage rat model of PD. This could indicate that the model is useful for examining mGluR4 agonists and other potential treatments of PD more fully, in a holistic sense, rather than the traditional methods of separating out the treatment of motor and non-motor symptoms. In conclusion, a systemically-administered agonist of mGluR4 showed promise in the treatment of neurodegeneration in an early-stage model of PD in rats. This appears to have a number of underlying mechanisms including some modulation of inflammation and also transcriptional changes to genes which have been shown to affect neurodegeneration and neuroprotection. Furthermore, this agonist also has anti-Parkinsonian potential without causing dyskinesia - mGluR4 is therefore a suitable and promising target for further research in PD.
Supervisor: Duty, Susan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available