A N-methyl-D-aspartate receptor-mediated neurotoxic effect of aspartate-based hydroxamate compounds in rat primary neuronal cultures.
In a previous study (Lockhart et al., Brain Res., 630 (1993) 32-40) we demonstrated a NMDA receptor-mediated neurotoxic effect for the anti-HIV drugs D-aspartate beta-hydroxamate and structurally related analogues in rat primary cortical neurons. Herein, we have examined the neurotoxic action and pharmacology of a novel series of hydroxamate compounds, with potential anti-HIV activity, in a similar paradigm. In this aim, the aspartate-based hydroxamates L-VHS.126 and its stereoisomer D-VHS.126 selectively destroyed (EC50 = 300 microM) rat primary neurons. The D-VHS.126 analogue, VHS.134 was also neurotoxic (EC50 = 450 microM) whereas VHS.129 and VHS.137, or the D-aspartate beta-hydroxamate analogues VHS.128, VHS.135, VHS.132 and VHS.127 or hydroxyurea demonstrated no significant neurotoxicity. The neurotoxic action of L- and D-VHS.126, and VHS.134 was attenuated with MK-801, CGS-19755 but not with CNQX. These observations demonstrate a potent NMDA receptor-mediated excitotoxic action for novel aspartate-based hydroxamate compounds, and further extends this series of potential hydroxamate-based anti-HIV drugs lacking neurotoxicity in vitro.
Lockhart
B P
BP
INSERM U-336, Ecole Nationale Supérieure de Chimie, Montpellier, France.
Hamedi-Sangsari
F
F
Vignon
J
J
Privat
A
A
Vila
J
J
D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001216:Asparagine / Q000031:analogs & derivatives* / Q000633:toxicity; D002478:Cells, Cultured; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D000998:Antiviral Agents; D016194:Receptors, N-Methyl-D-Aspartate; C024848:beta-aspartylhydroxamic acid; D001216:Asparagine