Abstract
Excessive glutamate neurotransmission has been implicated in neuronal injury in many disorders of the central nervous system (CNS), including human immunodeficiency virus (HIV)-associated dementia. Gp120IIIB is a strain of a HIV glycoprotein with specificity for the CXCR4 receptor that induces neuronal apoptosis in in vitro models of acquired immunodeficiency syndrome (AIDS)-induced neurodegeneration. Since the catabolism of the neuropeptide N-acetylaspartylglutamate (NAAG) by glutamate carboxypeptidase (GCP) II increases cellular glutamate, an event associated with excitotoxicity, we hypothesized that inhibition of GCP II may prevent gp120IIIB-induced cell death. Furthermore, through GCP II inhibition, increased NAAG may be neuroprotective via its agonist effects at the mGlu3 receptor. To ascertain the therapeutic potential of GCP II inhibitors, embryonic day 17 hippocampal cultures were exposed to gp120IIIB in the presence of a potent and highly selective GCP II inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). 2-PMPA was found to abrogate gp120IIIB-induced toxicity in a dose-dependent manner. Additionally, 2-PMPA was neuroprotective when applied up to 2 h after the application of gp120IIIB. The abrogation of apoptosis by 2-PMPA was reversed with administration of mGlu3 receptor antagonists and with antibodies to transforming growth factor (TGF)-β. Further, consistent with the localization of GCP II, 2-PMPA failed to provide neuroprotection in the absence of glia. GCP II activity and its inhibition by 2-PMPA were confirmed in the hippocampal cultures using radiolabeled NAAG and high-performance liquid chromatography (HPLC) analysis. Taken together, these data suggest that GCP II is involved in mediating gp120-induced apoptosis in hippocampal neurons and GCP II inhibitors may have potential in the treatment of neuronal injury related to AIDS.
Acknowledgment
This article was submitted in memory of Dr. Amos Bodner, MD.
The authors wish to acknowledge the expert technical assistance of Christopher Mauer, and the proficient assistance of Deborah Stoit.
Declaration of interest: This work was supported by grants from the NIH DA012121, DA13141, MH40165, NS33826, DK44840, and NS21442 to Richard J. Miller. Amos Bodner was partially supported by a fellowship for careers in clinical pharmacology from the Pharmaceutical Research and Manufacturers of America Foundation, as well as a gift from Guilford Pharmaceuticals, Inc. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.