Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?

Abstract

The type 5 metabotropic glutamate receptor, mGlu5, has been proposed as a potential therapeutic target for the treatment of several neurodegenerative diseases. In preclinical neurodegenerative disease models, novel allosteric modulators have been shown to improve cognitive performance and reduce disease-related pathology. A common pathological hallmark of neurodegenerative diseases is a chronic neuroinflammatory response, involving glial cells such as astrocytes and microglia. Since mGlu5 is expressed in astrocytes, targeting this receptor could provide a potential mechanism by which neuroinflammatory processes in neurodegenerative disease may be modulated. This review will discuss current evidence that highlights the potential of mGlu5 allosteric modulators to treat neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, this review will explore the role of mGlu5 in neuroinflammatory responses, and the potential for this G protein-coupled receptor to modulate neuroinflammation.

Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity

“…Several other mGluR5 regulated mechanisms could potentially modulate recovery after stroke, 16 , 88 such as changes in growth factor levels including BDNF, 71 , 89 brain inflammation 35 or axogenesis. 90 , 91 Further research is needed to understand the mechanisms underlying the enhancement of recovery by mGluR5 NAMs after stroke.…”

“…Importantly, because we show that mGluR5 is present in relevant regions of injured brain tissue in stroke patients, they may be amenable to therapeutic interventions. Still, outside of stroke, the clinical effects of mGluR5 NAMs in other brain disorders depend on context, dose and timing, 35 which has implications for the clinical trial design of these compounds in stroke recovery. Translating preclinical findings into successful clinical trials has generally been unsuccessful.…”

“…Under physiological conditions, mGluR5 modulates synaptic transmission and might regulate both Hebbian and homeostatic plasticity. 32–34 In pathological conditions, mGluR5 may contribute to maladaptive brain plasticity and persistent neurological dysfunctions 35 as observed in Parkinson’s disease, 36 fragile X syndrome (FXS) 37 and Alzheimer’s disease. 38 Negative allosteric modulators (NAMs) of mGluR5 have been in clinical trials as a potential therapeutic.…”

“… 38 Negative allosteric modulators (NAMs) of mGluR5 have been in clinical trials as a potential therapeutic. 35 …”

Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies

“…mGluRs are G-protein-coupled receptors that regulate glutamate neurotransmission. Activation of certain mGluR subtypes, particularly mGluR5, has been implicated in HD pathology [130,131]. Animal studies have shown that mGluR5 antagonists can activate autophagy through convergent mechanisms, promoting the clearance of mHTT aggregates and reducing neurodegeneration in HD models [132].…”