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 gp120IIIB-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 gp120IIIB 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.
|Original language||English (US)|
|Journal||Clinical Pharmacology and Therapeutics|
|State||Published - Dec 1 2001|
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