1-aminoindan-1,5-dicarboxylic acid and (S)-(+)-2-(3 '-carboxybicyclo[1.1.1] pentyl)-glycine, two mGlu1 receptor-preferring antagonists, reduce neuronal death in in vitro and in vivo models of cerebral ischaemia

Metabotropic glutamate (mGlu) receptors have been implicated in a number of physiological and pathological responses to glutamate, but the exact role of group I mGlu receptors in causing postischaemic injury is not yet clear. In this study, we examined whether the recently-characterized and relative ly selective mGlu1 receptor antagonists 1-aminoindan-1,5-dicarboxylic acid (AIDA) and (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG) could reduce neuronal death in vitro, following oxygen-glucose deprivation (OGD) in murine cortical cel land rat organotypic hippocampal cultures,and in viv o, after global ischaemia in gerbils. When present in the incubation medium during the OGD insult and the subsequent 24 h recover period, AIDA and CBP G significantly reduced neuronal death in vitro. The extent of protection w as similar to that observed with the nonselective mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine [(+)MCPG] and with typical ionotrop ic glutamate(iGlu) receptor antagonists. Neuroprotection was also observed when AIDA or CBPG were added only after the OGD insult was terminated. Neur onal injury was not attenuated by the inactive isomer (-)MCPG, but was sign ificantly enhanced by the nonselective mGlu receptor agonist (1S, 3R)-1-amo nocyclopentane-1,3-dicarboxylic acid [(1S, 3R)-ACPD] and the group I mGlu r eceptor agonist 3,5-dihydroxyphenylglycine (3,5-DHPG). The antagonists (+)M CPG, AIDA and CBPG were also neuroprotective in vivo, because i.c.v. admini stration reduced CA1 pyramidal cell degeneration examined 7 days following transient carotid occlusion in gerbils. Our results point to a role of mGlu 1 receptors in the pathological mechanisms responsible for postischaemic ne uronal death and propose a new target for neuroprotection.