Therapeutic potential of targeting glutamate receptors in Parkinson's disease

Abstract

Glutamate plays a complex role in many aspects of Parkinson's disease including the loss of dopaminergic neurons, the classical motor symptoms as well as associated non-motor symptoms and the treatment-related side effect, L-DOPA-induced dyskinesia. This widespread involvement opens up possibilities for glutamate-based therapies to provide a more rounded approach to treatment than is afforded by current dopamine replacement therapies. Beneficial effects of blocking postsynaptic glutamate transmission have already been noted in a range of preclinical studies using antagonists of NMDA receptors or negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), while positive allosteric modulators of mGlu4 in particular, although at an earlier stage of investigation, also look promising. This review addresses each of the key features of Parkinson's disease in turn, summarising the contribution glutamate makes to that feature and presenting an up-to-date account of the potential for drugs acting at ionotropic or metabotropic glutamate receptors to provide relief. Whilst only a handful of these have progressed to clinical trials to date, notably NMDA and NR2B antagonists against motor symptoms and L-DOPA-induced dyskinesia, with mGlu5 negative allosteric modulators also against L-DOPA-induced dyskinesia, the mainly positive outcomes of these trials, coupled with supportive preclinical data for other strategies in animal models of Parkinson's disease and L-DOPA-induced dyskinesia, raise cautious optimism that a glutamate-based therapeutic approach will have significant impact on the treatment of Parkinson's disease.