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Assessment of novel therapeutic approaches in the YAC128 mouse model of Huntington disease Pouladi, Mahmoud A.

Abstract

Huntington disease (HD) is a progressive disorder characterized by involuntary movements, emotional disturbances, and memory loss. There is currently no cure for HD. Accumulating evidence has implicated excitotoxicity, a process in which excessive signaling via the glutamate receptors results in neurotoxicity, in HD. The main aim of the studies presented was to evaluate the potential of small molecules known to target excitotoxicity-related pathways in the YAC128 mouse model of HD. We examined whether treatment with memantine, a clinically well-tolerated NMDA receptor antagonist, can improve the phenotype of YAC128 mice. We demonstrated that treatment with memantine results in improvements in motor function and rescues the striatal deficits in a dose-specific manner. Rasagiline is a selective inhibitor of monoamine oxidase type B (MAO-B) clinically approved for the treatment of Parkinson’s disease that has been shown to protect against a number of neurotoxic stimuli. We demonstrate that rasagiline protects against striatal lesioning in acute models of excitotoxicity and improves the motor function of the YAC128 mice. We next examined the effect of treatment with a combination of memantine and rasagiline on the phenotype of the YAC128 mice. We demonstrate that treatment with a combination of memantine and rasagiline provides early and sustained improvements in motor function and rescues striatal deficits in the YAC128 mice. Induction of a heat shock protein (HSP) response has been shown to be neuroprotective in models of excitotoxicity and polyglutamine-induced neurodegenerative disease. We examined whether treatment with arimoclomol, a compound shown to enhance the HSP response, can improve the phenotype of the YAC128 mice. Our findings demonstrate that treatment with arimoclomol does not lead to up-regulation of an HSP response or rescue of the behavioural and striatal deficits in the YAC128 mice. Finally, we characterize psychiatric disturbances in YAC128 mice, demonstrating that YAC128 mice exhibit depressive-like symptoms as assessed by the Porsolt forced swim test and the sucrose consumption test of anhedonia. These measures may be employed in assessing any anti-depressive effects of candidate treatments in preclinical therapeutic trials. Our findings suggest that targeting excitotoxicity may be a viable therapeutic approach in HD.

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