Development of Novel Glutamate Antagonists as Neural Protectants against Organophosphorus (OP) Compounds

Organophosphorus (OP) cholinesterase inhibitors, like sarin, cause severe toxic symptoms, including convulsions, coma, and death. Though the primary action of OP agents is well-characterized [i.e., irreversible inhibition of acetylcholinesterase (AChE), the primary metabolic enzyme of the cholinergic neurotransmitter acetylcholine], it has been difficult to identify and implement palliative therapies that effectively block the direct effects of OPs on AChE or prevent OP-induced seizures and convulsions. In fact, the convulsions resulting from OP intoxication present a significant problem for the medical treatment of military personnel and civilian populations exposed to nerve agents since they lead to profound brain damage and long-term psychiatric, motor and cardiovascular problems. This Phase II project aims to evaluate the ability of novel glutamate receptor antagonists to abrogate seizure-related behaviors in a rodent model of sarin intoxication. We will compare the efficacy of these agents with that of a benzodiazepine, midazolam, which is now in development as an anticonvulsant for military use. In parallel with our behavioral evaluations of these anticonvulsants we will perform biochemical experiments to test the hypothesis that effects of these compounds on glutamate receptor phosphorylation state in the brain represent a useful marker, and potential screening assay, for the anticonvulsant efficacy of novel anticonvulsant candidates.