Protective effects of N-methyl-D-aspartate receptor antagonism on VX-induced neuronal cell death in cultured rat cortical neurons

Exposure of the central nervous system to organophosphorus (OP) nerve agents induces seizures and neuronal cell death. Here we report that the OP nerve agent, VX, induces apoptoticlike cell death in cultured rat cortical neurons. The VX effects on neurons were concentrationdependent, with an IC50 of approximately 30 I,M. Blockade of N-methyl-D-aspartate receptors (NMDAR) with 50 pM D-2-amino-5phosphonovalerate (APV) diminished 30 wM VX-induced total cell death, as assessed by alamarBlueT"' assay and Hoechst staining. In contrast, neither antagonists of a-amino-3-hydroxy5-methylisoxazole-4-propionic acid receptors (AMPARs) nor metabotropic glutamate receptors (mG1uRs) had any effect on VX-induced neurotoxicity. VX-induced neuronal cell death could not be solely attributed to acetylcholinesterase (ACNE) inhibition, since neither the reversible pharmacological cholinesterase inhibitor, physostigmine, nor the muscarinic receptor antagonist, atropine, affected VX-induced cell death. Importantly, APV was found to be therapeutically effective against VX-induced cell death up to 2 h post VX exposure. These results suggest that NMDARs, but not AMPARs or mGluRs, play important roles in VX-induced cell death in cultured rat cortical neurons. Based on their therapeutic effects, NMDAR antagonists may be beneficial in the treatment of VX-induced neurotoxicities.