N-acetylated alpha-linked acidic dipeptidase converts N-acetylaspartylglutamate from a neuroprotectant to a neurotoxin

We previously reported that inhibition of the brain enzyme N-acetylated alp ha-linked acidic dipeptidase (NAALADase; glutamate carboxypeptidase II) rob ustly protects cortical neurons from ischemic injury. Since NAALADase hydro lyzes N-acetylaspartylglutamate (NAAG) to glutamate we hypothesized that in hibiting NAALADase would both decrease glutamate and increase NAAG. Increas ing NAAG is potentially important because NAAG is a metabotropic glutamate receptor agonist and an N-methyl-D-aspartate (NMDA) partial antagonist, bot h of which have previously been shown to be neuroprotective. To understand the likely effects of endogenous NAAG in the central nervous system, we hav e now investigated the activity of NAAG in primary cortical cultures while manipulating NAALADase activity. Under hydrolyzing conditions, when NAALADa se was active, NAAG had toxic effects that were blocked by NMDA and alpha-a mino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor a ntagonists and by NAALADase inhibition. NAAG's toxic effects were presumabl y due to the liberation of glutamate. Under nonhydrolyzing conditions, when NAALADase was inhibited, NAAG demonstrated neuroprotective effects against both NMDA toxicity and metabolic inhibition. In the case of NMDA-induced t oxicity, NAAG provided neuroprotection through its partial antagonist activ ity at the NMDA receptor. In the case of metabolic inhibition, NAAG had an additional neuroprotective effect mediated through its agonist properties a t the type II metabotropic glutamate receptor. These results indicate that NAAG might play an important role in the central nervous system, under cert ain pathological conditions, as a neurotoxin or as a neuroprotectant, depen ding on the activity of NAALADase.