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 analog ues in rat primary cortical neurons. Herein, we have examined the neur otoxic action and pharmacology of a novel series of hydroxamate compou nds, 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 (EC(50) = 300 mu M) rat primary neurons . The D-VHS.126 analogue, VHS.134 was also neurotoxic (EC(50) = 450 mu M) whereas VHS.129 and VHS.137, or the D-aspartate P-hydroxamate anal ogues VHS.128, VHS.135, VHS.132 and VHS.127 or hydroxyurea demonstrate d 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 CN QX. These observations demonstrate a potent NMDA receptor-mediated exc itotoxic action for novel aspartate-based hydroxamate compounds, and f urther extends this series of potential hydroxamate-based anti-HIV dru gs lacking neurotoxicity in vitro.