Abstract Chemical warfare nerve agents (CWNA) are increasingly used to attack civilians worldwide. Currently, we lack effective treatment for CWNA survivors. Until recently, preventing acute death due to CWNA exposure had taken a top priority. However, reports on the life-long health consequences of sarin attack survivors are beginning to emerge. Like organophosphates (OPs), CWNAs are cholinesterase inhibitors and potent seizurogenic agents. In animal models, acute CWNA/OP exposure induces status epilepticus (SE) and other cholinergic symptoms. The current medical countermeasures (MCM) such as atropine, oxime, and diazepam/midazolam control symptoms, but do not prevent long-term neurotoxicity and comorbidity, primarily due to persistent nitrooxidative stress, neuroinflammation, and neurodegeneration. We predict that a combination of neuroprotectant and MCM can prevent CWNA-induced long-term neurotoxicity. We propose to investigate the long-term neuroprotective and antiepileptogenic effects of a novel inhibitor of NADPH oxidase (NOX2), mitoapocynin, in rat diisopropylfluorophosphate (DFP) and a nerve agent soman models. As proof of concept, we demonstrated the neuroprotective and disease-modifying properties of NOX2 inhibitors in the rat DFP and the mouse Parkinson's disease (PD) and seizure models. Treating mice or rats with mitoapocynin before the induction of SE with kainate (KA) or DFP significantly prevented the onset of convulsive seizures suggesting its anti-seizure property. We further tested mitoapocynin and diapocynin in telemetry-implanted rats after inducing SE with KA or DFP and treating them with MCM. Both NOX2 inhibitors are blood-brain barrier permeable. They prevented epileptogenesis in >50% rats and significantly reduced reactive gliosis and neurodegeneration. Although we had tested the proof of concept for the role of NOX2 in the rat DFP model, the optimum dose of diapocynin used was too high (300 mg/kg), which cannot be extrapolated for human use. Therefore, we developed, characterized, tested in vivo, and patented (US8962600 B2) the mitoapocynin, which is effective at 10-30 times lesser dose than diapocynin. Our overarching hypothesis is that mitoapocynin counteracts CWNA-induced long-term neurodegeneration, epileptogenesis, and restores brain function. We will investigate this in both male and female rat DFP models (Specific Aim 1) and validate in soman model (Specific Aim 2). We will expose rats to DFP/soman, treat with MCM, and 2h later with mitoapocynin (30 mg/kg, oral) or vehicle twice daily for the first three days, and 6 weeks later conduct a battery of behavioral tests. We will implant a telemetry device to monitor SRS and disease progression/modification in real-time. To determine the protective effect of mitoapocynin, we will conduct brain histochemistry for neurodegeneration and neuroinflammation, nitro-oxidative stress assays, and multiplex assay for cytokines. Our proposal embodies a novel translational approach t...