Development of Pre- and Post-Exposure Neural Protectants Against Organophosphorus (OP) Compounds Based on Novel and Specific Biochemical Markers of OP

Exposure to organophosphorous (OP) cholinesterase inhibitors, used as nerve agents for bioterrorism, results in severe physiological symptoms, including convulsions, coma, and death. Though the primary action of OP agents is well-characterized [i.e., irreversible inhibition of acetylcholine (ACh) breakdown by its primary metabolic enzyme, acetylcholinesterase (AChE)], 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. The goal of the present proposal is to use state-of-the-art biochemical methods to identify intracellular signaling effects of sarin that are critical for the induction of nerve agent-induced seizures and convulsions and to use these identified substrates as a means to screen promising anti-convulsive therapies as anti-sarin treatments.