Group III metabotropic glutamate receptors as promising targets for neuroprotective therapy: Particular emphasis on the role of mGlu4 and mGlu7 receptors

There is still no effective treatment for central nervous system (CNS) pathologies, including cerebral ischemia, neurotrauma, and neurodegenerative diseases in which the Glu/GABA balance is disturbed with associated excitotoxicity. It is thus important to search for new efficacious therapeutic strategies. Preclinical studies on the role of metabotropic glutamate receptors (mGluRs) in neuroprotection conducted over the years show that these receptors may have therapeutic potential in these CNS disorders. However, clinical trials, especially for treating Parkinson's disease, have been unsatisfactory. This review focuses on the specific role of group III mGluRs in neuroprotection in experimental in vitro and in vivo models of excitotoxicity/neurotoxicity using neurotoxins as well as ischemia, traumatic brain injury, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's diseases, and multiple sclerosis. The review highlights recent preclinical studies in which group III mGluR ligands (especially those acting at mGluR4 or mGluR7) were administered after damage, thus emphasizing the importance of the therapeutic time window in the treatment of ischemic stroke and traumatic brain injury. From a clinical standpoint, the review also highlights studies using group III mGluR agonists with favorable neuroprotective efficacy (histological and functional) in experimental ischemic stroke, including healthy normotensive and-hypertensive rats. This review also summarizes possible mechanisms underlying the neuroprotective activity of the group III mGluR ligands, which may be helpful in developing more effective and safe therapeutic strategies. Therefore, to fully assess the role of these receptors in neuroprotection, it is necessary to uncover new selective ligands, primarily those stimulating mGlu4 and mGlu7 receptors.