DESCRIPTION (provided by applicant): The acute toxicity of OPs is primarily due to inhibition of acetylcholinesterase (AChE). Current therapy for OP poisoning requires resuscitation with the use of atropine, followed by administration of oximes to reactivate AChE, and benzodiazepines to mitigate neurological complications. However, these antidotes have limited effectiveness and between 10 and 40% of patients, depending on the responsible OP, still die even with intensive care support. Furthermore, acute failure of neuromuscular transmission leads to respiratory failure and profound weakness. This failure of the neuromuscular junction (NMJ) has recently been shown to occur within hours after severe poisoning. The purpose of this grant is to determine the physiologic and immunohistochemical efficacy of the nicotinic receptor antagonist pancuronium in preserving NMJ function and NMJ architecture in a novel rat model of parathion poisoning. This model will mimic the Intermediate Syndrome and consist of intensive care treatment with comprehensive medical therapy, including mechanical ventilation, atropine, 2-PAM, benzodiazepines, and vasopressors. Our central hypothesis is that pharmacologic targeting of the NMJ with pancuronium will improve muscle strength and NMJ structure in a rat model of acute parathion poisoning. Lastly, while these studies are critically applicable to chemical warfare and mass casualty situations, they are also applicable to isolated cases of severe OP poisoning that occur every day in the U.S. and abroad.

PUBLIC HEALTH RELEVANCE: If successful, the proposed research promises to improve public health by mitigating the acute and subacute toxic effects of OP pesticides after intentional or accidental poisoning.