N-acetylaspartylglutamate protects against transient focal cerebral ischemia in rats

The inhibition of N-acetylated alpha -linked acidic dipeptidase (NAALADase: glutamate carboxypeptidase II) has been previously shown to protect agains t ischemic injury presumably through mechanisms of decreasing glutamate and increasing N-acetylaspartylglutamate (NAAG). Preventing excessive glutamat e release is known to be neuroprotective. However, the role of increased NA AG is not clear. We used a middle cerebral artery occlusion model in rats t o investigate the neuroprotective effect of NAAG via its action as a metabo tropic glutamate (mGlu) receptor agonist. Rats received intracerebral injec tions of NAAG (1, 2, or 4 mu mol), or a co-injection of NAAG (2 mu mol) and the non-selective mGlu receptor antagonist, (R,S)-alpha -methyl-4-carboxyp henylglycine, (MCPG, 2 mu mol). Immediately after the treatment, the animal s received 2 h of middle cerebral artery occlusion followed by 22 h of repe rfusion. Treatment with 1 or 2 mu mol of NAAG significantly reduced total i nfarct volume. Treatment with MCPG partially attenuated the neuroprotective effect of NAAG, indicating that the protective effect of NAAG against isch emic injury may be in part mediated via activation of mGlu receptors. (C) 2 000 Elsevier Science B.V. All rights reserved.