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-A beta H), selectively destroys HIV-1 infected peripheral blood mononuclear cells, but produces anorexia and nausea during prolonged treatment to AIDS patients. Consequently, based on the structural similarity between D-A beta H and the excitotoxins L-aspartate and NMDA, we have investigated the potential neurotoxic action and pharmacology of D-A beta H and of a series of chemically related anti-tumor drugs on rat primary neuronal/glial cultures. In this aim, after a 30 min exposure to D-A beta H (1-2 mM), cortical neurons were selectively destroyed within 24 h. The stereoisomer L-A beta H (0.5-2 mM) was highly neurotoxic for both glial and neuronal cells in mixed cultures but demonstrated no toxicity in glial cell cultures alone. Furthermore, for a series of D-A beta H analogues, VHS.121 and VHS.122 demonstrated a reduced but significant neurotoxicity, whereas VHS.124 and VHS.125 showed no significant neurotoxic effect, and in the case of VHS.125 also prevented D-A beta H and glutamate-mediated neurotoxicity. The related anti-tumor drugs L- or D-glutamate gamma-monohydroxamate or keto-glutamate gamma-monohydroxamate (< or = 2 mM) were not neurotoxic for cortical neurons. The neurotoxic effect of D-A beta H and L-A beta H was attenuated by the NMDA antagonists MK-801, TCP, memantine, ifenprodil, pentamidine and CGS-19755. alpha-Difluoromethylornithine, an inhibitor of polyamine biosynthesis, also protected cultures against the neurotoxicity of L-A beta H and D-A beta H.(ABSTRACT TRUNCATED AT 250 WORDS)
Lockhart
B P
BP
INSERM U-336, Développement, Plasticité et Vieillissement du Système Nerveux, Ecole Nationale Supérieure de Chimie, Montpellier, France.
Vila
J
J
Hamedi-Sangsari
F
F
Privat
A
A
Vignon
J
J
D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives* / Q000633:toxicity; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
C024848:beta-aspartylhydroxamic acid; D016202:N-Methylaspartate; D001216:Asparagine