Group III and subtype 4 metabotropic glutamate receptor agonists: discovery and pathophysiological applications in Parkinson's disease

Abstract

Restoring the balance between excitatory and inhibitory circuits in the basal ganglia, following the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta, represents a major challenge to treat patients affected by Parkinson's disease (PD). The imbalanced situation in favor of excitation in the disease state may also accelerate excitotoxic processes, thereby representing a potential target for neuroprotective therapies. Reducing the excitatory action of glutamate, the major excitatory neurotransmitter in the basal ganglia, should lead to symptomatic improvement for PD patients and may promote the survival of DA neurons. Recent studies have focused on the modulatory action of metabotropic glutamate (mGlu) receptors on neurodegenerative diseases including PD. Group III mGlu receptors, including subtypes 4, 7 and 8, are largely expressed in the basal ganglia. Recent studies highlight the use of selective mGlu4 receptor positive allosteric modulators (PAMs) for the treatment of PD. Here we review the effects of newly-designed group-III orthosteric agonists on neuroprotection, neurorestoration and reduction of l-DOPA induced dyskinesia in animal models of PD. The combination of orthosteric mGlu4 receptor selective agonists with PAMs may open new avenues for the symptomatic treatment of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.