       Document 0613
 DOCN  M9460613
 TI    Neurotoxic effect of the anti-HIV drug D-aspartate beta-hydroxamate for
       rat primary neuronal cultures: attenuation by N-methyl-D-aspartate
       (NMDA) antagonists.
 DT    9404
 AU    Lockhart BP; Vila J; Hamedi-Sangsari F; Privat A; Vignon J; INSERM
       U-336, Developpement, Plasticite et Vieillissement du; Systeme Nerveux,
       Ecole Nationale Superieure de Chimie,; Montpellier, France.
 SO    Brain Res. 1993 Dec 10;630(1-2):32-40. Unique Identifier : AIDSLINE
       MED/94163493
 AB    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)
 DE    Animal  Asparagine/*ANALOGS & DERIVATIVES/TOXICITY  Cells, Cultured
       Cerebral Cortex/*DRUG EFFECTS/PATHOLOGY  HIV Infections/*DRUG
       THERAPY/PATHOLOGY  N-Methylaspartate/*ANTAGONISTS & INHIB  Neurons/*DRUG
       EFFECTS  Rats  Rats, Sprague-Dawley  Support, Non-U.S. Gov't  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

