Neuroprotection afforded by NAAG and NAALADase inhibition requires glial cells and metabotropic glutamate receptor activation

N-acetylated-alpha -linked-acidic-dipeptidase (NAALADase or glutamate carbo xypeptidase II) cleaves the neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to glutamate and N-acetyl-aspartate (NAA). Previously, NAAG and 2-(phospho nomethyl)-pentanedioic acid (2-PMPA), a potent and selective NAALADase inhi bitor, were found to be neuroprotective in neuronal/glial co-cultures and i n animals following transient middle cerebral artery occlusion. In this rep ort, we examined the involvement of glial cells and metabotropic glutamate (mGlu) receptors in neuroprotection mediated by NAAG and 2-PMPA in an in vi tro model of metabolic inhibition. Neuroprotection of neuronal/glial co-cul tures by both NAAG and 2-PMPA, against metabolic inhibition, was significan tly higher than neuroprotection in the absence of glia. Similarly, (2S,2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV), a selective group II m Glu receptor agonist, was less neuroprotective in the absence of glia. Sele ctive group II mGlu receptor antagonists and (S)-alpha -methyl-4-carboxyphe nylglycine (MCPG), a non-selective mGlu receptor antagonist, reduced the pr otection afforded by both NAAG and 2-PMPA when using neuronal/glial co-cult ures. In contrast, groups I and III mGlu receptor antagonists did not affec t NAAG or 2-PMPA neuroprotection. These results underscore the critical inv olvement of glia and group II mGlu receptors in NAAG and 2-PMPA-mediated ne uroprotection. (C) 2001 Elsevier Science B.V. All rights reserved.