A number of characteristics distinguish TETS and organophosphorus (OPs) cholinesterase inhibitors as credible chemical threat agents. 1) These agents can be easily manufactured on a large scale. 2) They are widely available in some countries even though banned in the US. 3) Exposure to either TETS or OPs dose dependently results in lethality or profound and sustained damage to the brain. In rodents, acute TETS or OP intoxication elicits delayed neuronal injury as evidenced by increased apoptosis and oxidative stress in the CNS that persists for up to several days following exposure. In humans, indivuduals that survive acute TETS or OP intoxication often experience significant brain damage. A limited number of therapeutic agents are available to prevent mortality induced by OP threat agents but these do not sufficiently protect against brain injury. Therapeutic approaches for TETS intoxication are less well known. To address these gaps, Core B will synthesize TETS and an inactive analog to be used as a negative control in mechanistic studies, as well as characterize and validate primary standard stocks of TETS, DFP and parathion. This will enable Projects 1-3 to advance applied therapeutic and mechanistic knowledge on these agents. Furthermore we will synthesize, characterize, test and optimize the pharmacokinetic (PK) properties and CNS penetration of two distinct classes of therapeutic agents, sEH inhibitors and KCa2 channel activators. Overall, the successful realization of the proposed aims in Core B is likely to improve therapeutic approaches for the treatment of acute OP and TETS intoxication by providing novel therapeutics for physicians and emergency first-responders to effectively intervene in cases of human intoxication with these seizurogenic chemical threat agents.
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