Counter Measures Against Acetylcholine Receptor Activated Status Epilepticus

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DESCRIPTION (provided by applicant): The overall goal of this research project is to respond to the CounterACT RFA by developing new, safe and effective therapeutic agents that will act as counter measures against the damage to the brain caused by status epilepticus (SE) produced by result of exposure to the anticholinesterase nerve agents (gases) identified in the RFA as higher priority chemical threats that represent toxic chemicals that could be used in a terrorist attack against civilians or could be released at toxic levels by an accident or natural disaster. This study is focused on developing drugs that can stabilize and protect the brain during and after SE to allow for additional time to control the seizures and to prevent or reverse the devastating effects of SE. SE is a major medical and neurological emergency that is associated with a significant morbidity and mortality and is a common result of exposure to the anticholinesterase nerve agents. The research proposed in this study will use the rodent pilocarpine model of SE that has been shown to produce SE in an essentially identical manner to nerve agents as an animal model to develop medical counter measures that can prevent the acute mortality and long-term morbidity from SE, including the development of neuronal death, epilepsy, and cognitive impairment. Aim 1: Determine whether ketamine and/or dantrolene can prevent the development of the Ca2+ plateau after SE when administered during and after SE. Hypothesis: The Ca2+ plateau from SE can be prevented or reversed by treatment during or after SE with ketamine and/or dantrolene. Aim 2: Determine whether ketamine and/or dantrolene prevent neuronal loss and decrease mortality when administered during and after SE. Hypothesis: Ketamine and/or dantrolene can decrease or prevent neuronal loss and mortality from SE when administered during or after SE. Aim 3: Determine the effectiveness of ketamine and/or dantrolene in blocking the development of AE after SE. Hypothesis: Ketamine and/or dantrolene given during or after SE can prevent the development of AE following SE. Aim 4: Determine the effectiveness of ketamine and/or dantrolene in preventing cognitive loss after SE. Hypothesis: Ketamine and/or dantrolene during or after SE will significantly reduce cognitive loss following SE. The results of this study may provide effective counter measures to protect the brain from nerve agent exposure. The preliminary results indicate that it is possible to prevent brain injury form SE.