Modulation of metabotropic glutamate receptors as potential treatment for acute and chronic neurodegenerative disorders.

Abstract

It is well established that in both animal models and humans, traumatic or ischemic insults to the brain or spinal cord cause an excessive release of excitatory amino acids, including glutamate. Moreover, multiple in vivo and in vitro studies show that excessive release of glutamate, and subsequent activation of ionotropic (iGluRs) and metabotropic (mGluRs) classes of glutamate receptors, cause neuronal cell death through either necrosis or apoptosis. Although studies in adult animals have demonstrated the neuroprotective effects of inhibiting iGluRs following central nervous system injury, results from human trials have been disappointing. Furthermore, treatment with iGluR antagonists alone can exacerbate apoptotic cell death in the developing brain. Recently, an alternative approach has examined the modulatory effects of mGluRs on excitotoxicity and neuronal cell death. Experimental studies have shown that modulation of all groups (I, II, III) of mGluR can be neuroprotective, and that effects across groups may be additive. Group I mGluR includes mGluR1 and mGluR5. Although these receptors show certain common signal transduction pathways, activation or inhibition of these two receptors have very different actions on necrotic and apoptotic neuronal cell death. Recent work has shown that activation of mGluR5 significantly attenuates neuronal apoptosis in a variety of model systems. Given the proposed role of apoptotic cell death in both acute and chronic neurodegenerative disorders, these observations suggest that this receptor may be an interesting novel target for the development of effective neuroprotective treatment.