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.