The overall goal of the current research is to develop a novel class of therapeutics that will mitigate mortality and morbidity caused by acute exposure to parathion, an organophosphate insecticide that is considered a high priority chemical threat. The toxicity of parathion is dependent on its metabolism by the cytochrome P450 system to an active metabolite, paraoxon. By inhibiting P450-mediated generation of paraoxon, progressive toxicity can be prevented or reversed. Ongoing research in our laboratory in the field of redox chemistry has led to the identification of a candidate therapeutic that is a highly effective inhibitor of the P450 system. This drug, which has very low toxicity, is currently undergoing advanced clinical trials for other diseases and has been approved by the FDA for other indications. Use of an FDA approved drug will greatly reduce the time required for regulatory approval should the proposed studies demonstrate that our candidate therapeutic is effective in counteracting parathion toxicity. Our studies represent a 'proof-of-principle'proposal designed to generate Preliminary Data on the efficacy of our drug;results from these studies will enable the development of a competitive application for more extensive support from the CounterACT program.
Our specific aims are to identify the precise site of action of our drug in the cytochrome P450 system and to test its efficacy in mitigating parathion toxicity in a rodent model. Success of this proposal may lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat.

Public Health Relevance

There is increasing concern that toxic chemicals could be released by a deliberate terrorist attack, or by accident or natural disaster. One readily obtainable toxic chemical that is considered of particular risk is parathion, an organophosphate insecticide. Parathion is a widely used agricultural chemical that becomes a toxic nerve agent once absorbed into the body where it is metabolized to a reactive metabolite called paraoxon. A major site of action for paraoxon is the enzyme acetylcholinesterase;proper functioning of this enzyme is crucial for normal nerve cell activity and its inhibition can be fatal. There are several treatments for organophosphate poisoning including atropine, a competitive antagonist of acetylcholine, and pralidoxime which binds to organophosphate-inactivated acetylcholinesterase and regenerates the enzyme. Both of these agents have limitations and there remains a pressing need to develop new more efficacious therapies for parathion poisoning. Success of this proposal will lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MDCN-J (50))
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Yeung, David
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University of Medicine & Dentistry of NJ
Public Health & Prev Medicine
Schools of Medicine
United States
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Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A et al. (2016) Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione. Ann N Y Acad Sci 1378:80-86
Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A et al. (2015) Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication. Toxicol Appl Pharmacol 288:114-20
Hossain, Muhammad M; DiCicco-Bloom, Emanuel; Richardson, Jason R (2015) Hippocampal ER stress and learning deficits following repeated pyrethroid exposure. Toxicol Sci 143:220-8
Yang, Shaojun; Jan, Yi-Hua; Mishin, Vladimir et al. (2015) Sulfa drugs inhibit sepiapterin reduction and chemical redox cycling by sepiapterin reductase. J Pharmacol Exp Ther 352:529-40
Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir et al. (2014) Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats. Toxicol Appl Pharmacol 279:43-52
Richardson, Jason R; Roy, Ananya; Shalat, Stuart L et al. (2014) Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol 71:284-90
Bradner, Joshua M; Suragh, Tiffany A; Wilson, W Wyatt et al. (2013) Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: role of dopamine handling in neurotoxicity. Exp Neurol 241:138-47
Inamdar, Arati A; Hossain, Muhammad M; Bernstein, Alison I et al. (2013) Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration. Proc Natl Acad Sci U S A 110:19561-6
Richardson, Jason R; Hossain, Muhammad M (2013) Microglial ion channels as potential targets for neuroprotection in Parkinson's disease. Neural Plast 2013:587418
Hossain, Muhammad M; Sonsalla, Patricia K; Richardson, Jason R (2013) Coordinated role of voltage-gated sodium channels and the Na+/H+ exchanger in sustaining microglial activation during inflammation. Toxicol Appl Pharmacol 273:355-64

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