Chapter 14 Metabotropic glutamate receptors and neurodegeneration

Abstract

Metabotropic glutamate (mGlu) receptors, which exert a modulatory effect on excitatory synaptic transmission, are considered as potential targets for neuroprotective drugs and the advent of potent and centrally available subtype-selective ligands has lead to an extensive investigation of the role of individual mGlu receptor subtypes in neurodegeneration . Pharmacological blockade of mGlu I or -5 receptors or pharmacologica l activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlul receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of NMDA receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes, suggesting a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's disease (AD). MGlu2/3 receptor agonists inhibit glutamate release, and also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of eNS disorders . Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders.