GCP II inhibition rescues neurons from gp120IIIB-induced neurotoxicity.
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 mGlu(3) 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 mGlu(3) receptor antagonists and with antibodies to transforming growth factor (TGF)-beta. 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.
Thomas
Ajit G
AG
Brain Science Institute, NeuroTranslational Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Bodner
Amos
A
Ghadge
Ghanashyam
G
Roos
Raymond P
RP
Slusher
Barbara S
BS
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C402107:2-(phosphonomethyl)pentanedioic acid; D004151:Dipeptides; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D018094:Receptors, Metabotropic Glutamate; D016212:Transforming Growth Factor beta; C514793:gp120 protein, Human immunodeficiency virus 1; C102718:metabotropic glutamate receptor 3; C027172:isospaglumic acid; D043425:Glutamate Carboxypeptidase II