The main goal of this CounterACT R21 (exploratory) project is to determine the therapeutic potential of epigenetic therapy in attenuating subchronic and long-term neurological effects from acute organophosphate pesticide 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 a progression from miosis to seizures and status epilepticus, and then to death due to respiratory failure. If one survives this cholinergic crisis, there is usually damage to the brain and chronic neurological dysfunction. However, there are no treatment options available to prevent or mitigate these devastating long-term effects of OPNAs. A variety of agents targeting excitotoxicity, oxidation, and inflammation have been proposed, but epigenetic agents are not widely studied in OPNAs. Epigenetics refers to specific changes in gene expression mediated by chromatin-based mechanisms in response to environmental cues. In this project, we seek to identify an epigenetic intervention to limit long-term effects following OPNAs, with the ultimate goal of identifying a promising drug for common neuroprotection. 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 based on the hypothesis that acute OPNA neurotoxicity imparts long-lasting activation of the epigenetically- regulated HDAC pathway and therefore, selective HDAC inhibition prevents long-term neurodegeneration and neurological dysfunction. We will test this hypothesis by utilizing two FDA-approved drugs:
(Aim 1) To determine whether HDAC inhibitors sodium butyrate and vorinostat prevents or attenuates long-term neurodegeneration and neurological dysfunction following acute DFP exposure in rats;
and (Aim 2) To determine whether HDAC inhibitors sodium butyrate and vorinostat prevents or attenuates long-term neurodegeneration and neurological dysfunction following acute soman exposure in rats. Test drugs will be tested as per the NIH rigor criteria in a dose-related design in male and females for 2 weeks and behavior/neuropathology will be checked at 3 months post-exposure. The project will be implemented as per the ?go/no-go? milestones plan. Two primary outcome measures will be addressed for therapy effectiveness: (i) chronic neuroprotectant efficacy; and (ii) prevention of neurological 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 will provide ?proof-of-efficacy? of a ground-breaking therapy with two FDA-approved drugs with promising potential to limit 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.
Nerve agents are chemical warfare agents that rapidly result in seizures, brain injury and death. Survivors suffer from devastating long-term neurological and behavioral dysfunction as evident from Japan and Syrian chemical incidents. In this project, HDAC-based epigenetic intervention is proposed as a novel therapy that can effectively reduce short and long-term brain damage from acute exposure to nerve agents, specifically to test the potential of two FDA-approved drugs (sodium butyrate and vorinostat) as preventative medical countermeasures. Thus, epigenetics is a revolutionary and powerful strategy for finding new neuroprotectants for long-term effects of chemical exposure.
| Wu, Xin; Kuruba, Ramkumar; Reddy, Doodipala Samba (2018) Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents. J Pharmacol Exp Ther 367:302-321 |
| Kuruba, Ramkumar; Wu, Xin; Reddy, Doodipala Samba (2018) Benzodiazepine-refractory status epilepticus, neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication. Biochim Biophys Acta Mol Basis Dis 1864:2845-2858 |
