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Keywords:

  • Alzheimer's disease;
  • glutamate;
  • group III mGlu receptor;
  • neuroinflammation;
  • neuroprotection;
  • Parkinson's disease

Abstract

Thumbnail image of graphical abstract

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.

We review the neuroprotective and symptomatic effects of targeting group III mGlu receptors in neurodegenerative disease: Excess extracellular glutamate causes overactivation of NMDA receptors resulting in excitotoxicity. Externalization of phosphatidylserine stimulates phagocytosis of neurons by activated microglia, which contribute to damage through glutamate and pro-inflammatory factor release. Reactive astrocytes produce cytotoxic factors enhancing neuronal cell death. Activation of group III mGlu receptors by glutamate and/or mGlu receptor ligands results in inhibition of glutamate release from presynaptic terminals and microglia, reducing excitotoxicity. Astrocytic glutamate uptake is increased and microglia produce neurotrophic factors.