Neuroprotective and symptomatic effects of targeting group III mGlu receptors in neurodegenerative disease

Neurodegenerative disorders possess common pathological mechanisms, such as protein aggregation, inflammation, oxidative stress (OS) and excitotoxicity, raising the possibility of shared therapeutic targets. As a result of the selective cellular and regional expression of group III metabotropic glutamate (mGlu) receptors, drugs targeting such receptors have demonstrated both neuroprotective properties and symptomatic improvements in several models of neurodegeneration. In recent years, the discovery and development of subtype‐selective ligands for the group III mGlu receptors has gained pace, allowing further research into the functions of these receptors and revealing their roles in health and disease. Activation of this class of receptors results in neuroprotection, with a variety of underlying mechanisms implicated. Group III mGlu receptor stimulation prevents excitotoxicity by inhibiting glutamate release from neurons and microglia and increasing glutamate uptake by astrocytes. It also attenuates the neuroinflammatory response by reducing glial reactivity and encourages neurotrophic phenotypes. This article will review the current literature with regard to the neuroprotective and symptomatic effects of group III mGlu receptor activation and discuss their promise as therapeutic targets in neurodegenerative disease.