NAALADase inhibition reduces GP120_IIIB-induced neurotoxocity

N-acetyl-aspartyl glutamate (NAAG), a neuropeptide of glutamatergic pathways, is released from neurons after depolarization and is both an agonist at metabotropic glutamate receptors and a mixed agonist/antagonist at the NMDA receptor; its hydrolysis by glutamate carboxypeptidase II (NAALADase), expressed in astrocyte glial cells, releases N-acetyl-aspartate and glutamate. We hypothesize that inhibiting the neuropeptidase would provide neuroprotection from gp120_IIIB-induced apoptosis by both increasing NAAG and decreasing glutamate levels, the latter strongly implicated in the pathogenesis of HIV dementia. We tested 2-(phosphonomethyl) pentanedioic acid (2-PMPA), an inhibitor of NAALADase, in cultures of rat pyramidal hippocampal neurons grown in close juxtaposition to an astrocyte feeder layer. On DIV7, cells were treated with gp120_IIIB with or without concomitant administration of drug. Apoptosis was then assessed by nuclear morphology visualized with the chromatin stain Hoechst 33342 on DIV11. 2-PMPA was demonstrated to protect against injury, reducing apoptosis in a concentration-dependent manner maximal at 1 μM. These data indicate that NAALADase inhibition may have therapeutic utility in HIV dementia as well as in neurological disorders characterized by excessive excitatory amino acid transmission.