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Title: Targeting muscarinic receptor subtypes as a therapeutic approach in dystonia and Parkinson's disease
Author: Klisko, Dominika Maria
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
Anticholinergics show therapeutic utility in the treatment of some types of dystonia and in Parkinson’s disease, however, this is accompanied by wide range of unpleasant side effects, including dry-mouth. It has been proposed that muscarinic M4 receptors, located in the striatum, could be a novel therapeutic target to minimise involuntary movements and improve parkinsonian disability without producing unfavourable peripheral side effects. The effect of muscarinic antagonists with different relative selectivity for receptor subtypes, including a novel highly selective muscarinic antagonist for the M4 subtype, have been investigated using the pilocarpine-induced purposeless chewing model of dystonia in rats and MPTP-treated common marmoset model of PD. The peripheral effects of these drugs were assessed on pilocarpine-induced saliva secretion in rats. Pilocarpine purposeless chewing was significantly inhibited by centrally but not peripherally acting anticholinergics including the novel M4 selective antimuscarinic. It was confirmed that M1/M3 selective antimuscarinics are important in the onset of dry-mouth, and that this effect was peripherally mediated. Moderate suppression of salivation was also observed with M1 and M2 antimuscarinics, but not with the selective M4 antagonist. This suggests that selective blockade of muscarinic M4 receptors may have a role in dystonia without accompanying peripheral side effects. Interestingly, in MPTP-treated marmosets, co-administration of clinically used centrally acting anticholinergics alone and in combination with L-DOPA resulted in the expected improvement of locomotor activity and motor disability but also enhanced expression of L-DOPA-induced dyskinesia. By contrast, selective muscarinic M4 antagonist showed no significant improvement in locomotion and motor disability either alone or in combination with L-DOPA and did not reduce the expression of L-DOPA-induced dyskinesia, however, extended duration of dystonia. Overall, these studies support the idea that cholinergic system plays a role in mediation of motor control, and that selective antagonism of M4 receptors may reduce dystonia without inducing peripheral side effects, however, the lack of effect on motor function and the increase in drug-induced dystonia in the Parkinson’s disease model suggest no position in this disease.
Supervisor: Salvage, Sarah ; Jenner, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.718605  DOI: Not available
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