The impact of metabotropic glutamate receptors into active neurodegenerative processes: A “dark side” in the development of new symptomatic treatments for neurologic and psychiatric disorders

- mGlu receptor PAMs and NAMs are drug candidates for the treatment of CNS disorders.
- We discuss how mGlu drugs influence mechanisms of neurotoxicity and neuroprotection.
- We discuss how this influences the choice of the best drug to be used in the clinic.

Metabotropic glutamate (mGlu) receptor ligands are under clinical development for the treatment of CNS disorders with high social and economic burden, such as schizophrenia, major depressive disorder (MDD), and Parkinson's disease (PD), and are promising drug candidates for the treatment of Alzheimer's disease (AD). So far, clinical studies have shown symptomatic effects of mGlu receptor ligands, but it is unknown whether these drugs act as disease modifiers or, at the opposite end, they accelerate disease progression by enhancing neurodegeneration. This is a fundamental issue in the treatment of PD and AD, and is also an emerging theme in the treatment of schizophrenia and MDD, in which neurodegeneration is also present and contribute to disease progression. Moving from in vitro data and preclinical studies, we discuss the potential impact of drugs targeting mGlu2, mGlu3, mGlu4 and mGlu5 receptor ligands on active neurodegeneration associated with AD, PD, schizophrenia, and MDD. We wish to highlight that our final comments on the best drug candidates are not influenced by commercial interests or by previous or ongoing collaborations with drug companies.This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.