Targeting metabotropic glutamate receptors for symptomatic and disease-modifying treatment in Parkinson's disease

Degeneration of substantia nigra pars compacta dopaminergic neurons is the "hallmark" of Parkinson's disease (PD) and is responsible for motor signs. Other neurotransmitter systems are responsible for non-motor symptoms that may precede by decades the clinical onset of motor symptoms. The pathophysiology is complex and neurodegeneration involves excitotoxicity mechanisms and neuroinflammation. L-DOPA is the "gold" symptomatic therapy but does not halt the progression of the disease. Therefore, neuroprotective strategies are highly demanded. Metabotropic glutamate (mGlu) receptors have emerged as potential pharmacological targets because they modulate glutamatergic, GABAergic, and dopaminergic neurotransmissions, and have been implicated in mechanisms of neurodegeneration and neuroinflammation. Thus, mGlu receptors represent valuable targets for the development of new disease-modifying and symptomatic therapies for PD. This review highlights the role of individual mGlu receptor subtypes in the pathophysiology of motor and non-motor symptoms of PD and in mechanisms that contribute to the progression of the disease.