NEUROTOXIC EFFECT OF THE ANTI-HIV DRUG D-ASPARTATE BETA-HYDROXAMATE FOR RAT PRIMARY NEURONAL CULTURES - ATTENUATION BY N-METHYL-D-ASPARTATE(NMDA) ANTAGONISTS

The anti-tumor drug D-aspartate beta-hydroxamate (D-AbetaH), selective ly destroys HIV-1 infected peripheral blood mononuclear cells, but pro duces anorexia and nausea during prolonged treatment to AIDS patients. Consequently, based on the structural similarity between D-AbetaH and the excitotoxins L-aspartate and NMDA, we have investigated the poten tial neurotoxic action and pharmacology Of D-AbetaH and of a series of chemically related anti-tumor drugs on rat primary neuronal/glial cul tures. In this aim, after a 30 min exposure to D-AbetaH (1-2 mM), cort ical neurons were selectively destroyed within 24 h. The stereoisomer L-AbetaH (0.5-2 mM) was highly neurotoxic for both glial and neuronal cells in mixed cultures but demonstrated no toxicity in glial cell cul tures alone. Furthermore, for a series of D-AbetaH analogues, VHS.121 and VHS.122 demonstrated a reduced but significant neurotoxicity, wher eas VHS. 124 and VHS. 125 showed no significant neurotoxic effect, and in the case of VHS.125 also prevented D-AbetaH and glutamate-mediated neurotoxicity. The related anti-tumor drugs L- or D-glutamate gamma-m onohydroxamate or keto-glutamate gamma-monohydroxamate (less-than-or-e qual-to 2 mM) were not neurotoxic for cortical neurons. The neurotoxic effect Of D-AbetaH and L-AbetaH was attenuated by the NMDA antagonist s MK-801, TCP, memantine, ifenprodil, pentamidine and CGS-19755. Alpha -Difluoromethylornithine, an inhibitor of polyamine biosynthesis, also protected cultures against the neurotoxicity Of L-AbetaH and D-AbetaH . The pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainat e receptor antagonist, CNQX only partially delayed L-AbetaH and D-Abet aH neurotoxicity. These data suggest that the neurotoxic effect Of L-A betaH and D-AbetaH is mediated primarily via a NMDA receptor-induced e xcitotoxic effect. However, it is not fully established whether the si de-effects observed during D-AbetaH treatment are related exclusively to its neurotoxic action in vitro. The co-administration of D-AbetaH w ith clinically tolerated NMDA antagonists or the use of amino acid bas ed anti-tumor drugs lacking a neurotoxic effect, could eliminate some of the drug-related side effects, and may represent a novel therapeuti c strategy in the treatment of AIDS.