The neuroprotective and behavioural effects of group III metabotropic glutamate receptor ligands in rodent models of Parkinson’s disease

Abstract

Current therapies for Parkinson's disease are able to ameliorate the symptoms in the early stages, however as the disease progresses, they become less effective and patients often develop debilitating side effects. There is currently a significant unmet need for disease modifying or neuroprotective drugs to slow the rate of disease progression and provide long-term symptomatic relief. Novel therapeutics that can provide symptomatic relief whilst attenuating the ongoing neurodegeneration are therefore sought. The targeting of metabotropic glutamate (mGlu) receptors has become a therapeutic focus in recent years. The group III mGlu receptors are the focus of this thesis as they currently hold the most therapeutic promise, with evidence suggesting activation of these receptors not only modulates aberrant neurotransmission in the basal ganglia to provide symptom relief, but also provides neuroprotective effects in the nigrostriatal system through a variety of mechanisms. Recent advances in the development of subtype-selective ligands that cross the blood-brain barrier provides the ability to explore the variety of functions associated with targeting individual group III mGlu receptor subtypes in a clinically relevant manner. In order to determine the potential of these receptors as suitable targets for novel therapies, the antiparkinsonian activity and neuroprotective effects of group III mGlu receptor subtypes were investigated using two novel selective ligands in the lactacystin model, which features altered protein accumulation, progressive neuronal death and development of motor deficits. Neither ligand reduced motor symptoms effectively, and no robust neuroprotection was detected. Potential anti-inflammatory mechanisms of one compound were then investigated in vivo and in vitro but showed no clear effect. Selectively targeting group III mGlu receptors did not hold the neuroprotective or antiparkinsonian potential that was initially predicted. Collectively, these studies demonstrate the importance of testing therapies in a variety of models demonstrating different aspects of disease pathogenesis.