Epigenetic Attenuation of Long-Term Effects of Nerve Agents
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The main goal of this CounterACT R21 (exploratory) project is to determine the therapeutic potential ofepigenetic therapy in attenuating subchronic and long-term neurological effects from acute organophosphatepesticide and nerve agent (OPNA) exposure. Although the acute lethal effects of OPNAs are well described, non-lethal short- and long-term effects remain unclear. Immediately after exposure, nerve agent intoxication leads to aprogression from miosis to seizures and status epilepticus, and then to death due to respiratory failure. If one survivesthis cholinergic crisis, there is usually damage to the brain and chronic neurological dysfunction. However, there areno treatment options available to prevent or mitigate these devastating long-term effects of OPNAs. A variety ofagents targeting excitotoxicity, oxidation, and inflammation have been proposed, but epigenetic agents are not widelystudied in OPNAs. Epigenetics refers to specific changes in gene expression mediated by chromatin-basedmechanisms in response to environmental cues. In this project, we seek to identify an epigenetic intervention tolimit long-term effects following OPNAs, with the ultimate goal of identifying a promising drug for commonneuroprotection. The histone deacetylation (HDAC) pathway represents a logical target for such intervention,because HDACs regulate specific physiological functions in the brain. The proposed epigenetic therapy is basedon the hypothesis that acute OPNA neurotoxicity imparts long-lasting activation of the epigenetically-regulated HDAC pathway and therefore, selective HDAC inhibition prevents long-term neurodegenerationand neurological dysfunction. We will test this hypothesis by utilizing two FDA-approved drugs: (Aim 1) Todetermine whether HDAC inhibitors sodium butyrate and vorinostat prevents or attenuates long-termneurodegeneration and neurological dysfunction following acute DFP exposure in rats; and (Aim 2) To determinewhether HDAC inhibitors sodium butyrate and vorinostat prevents or attenuates long-term neurodegeneration andneurological dysfunction following acute soman exposure in rats. Test drugs will be tested as per the NIH rigorcriteria in a dose-related design in male and females for 2 weeks and behavior/neuropathology will be checked at 3months post-exposure. The project will be implemented as per the “go/no-go†milestones plan. Two primary outcomemeasures will be addressed for therapy effectiveness: (i) chronic neuroprotectant efficacy; and (ii) prevention ofneurological and behavioral deficits. The primary measures of neuroprotection include extent of neurodegeneration,neuroinflammation, neurogenesis, and mossy fiber sprouting. Key neurological outcomes include epileptic seizures,memory deficits, depression, anxiety behavior, and neurological/motor deficits. The outcome of this project willprovide “proof-of-efficacy†of a ground-breaking therapy with two FDA-approved drugs with promising potential tolimit long-term effects of OPNAs in humans. Thus, the overall impact of the outcome is enormous for civilians,especially in developing a post-exposure medical countermeasure for chemical agents.
