Impaired Sleep as a Target for Intervention Following Acute Organophosphate Intoxication

Organophosphate cholinesterase inhibitors (OPs) were developed as agricultural insecticides and adapted to function as chemical weapons. OPs inhibit the acetylcholinesterase enzyme and acute intoxication can lead to a cholinergic crisis, status epilepticus (SE) and, for individuals who survive, the development of spontaneous recurrent seizures (SRS) and cognitive deficits. The current CounterACT PAR-24-030, supports research related to the 1) evaluation of the natural history to 2) elucidate mechanisms related to long-term effects of acute- intoxication, and in particular the development of SRS and cognitive dysfunction, that will 3) identify relevant biomarkers to predict long-term outcomes and 4) identify new targets for therapeutic intervention. To date, little is known regarding the acute- or long-term effects of acute-OP intoxication on sleep architecture. In the field of epilepsy in general, the link between seizures and sleep disruption is complex, but well documented. Epilepsy and vigilance stages show a bi-directional relationship, with epilepsy disrupting sleep, and sleep disruption promoting seizures. Vigilance stages and seizures are each characterized by signature cortical electrical activity. Moreover, it is suggested that sleep-wake deficits are, in part, responsible for cognitive deficits observed in patients with epilepsy disorders. In fact, sleep enhancement is being pursued as an interventional strategy to reduce the burden of the epileptic syndrome. We hypothesize that sleep disruptions in the days-to-months following acute intoxication with the OP diisopropylfluourophosphate (DFP) play a key role in the development and maintenance of lasting pathophysiology including sleep disorders, seizures and cognitive dysfunction. We further hypothesize that restoring a normal sleep-wake cycle will be protective, preventing the development of the worst outcomes when provided acutely, and, in the absence of early intervention, counteracting symptoms when delivered chronically. In testing our hypotheses, we will necessarily assess each of the four topic areas related to the CounterACT RFA as described above. Specifically, we will determine whether acute intoxication with DFP leads to dynamic changes in sleep architecture in the days-to-months post-intoxication (natural history; goal 1) and predict that the animals with greater sleep disturbance experiencing prolonged cognitive and seizure disorders (sleep as a mechanism; goal 2). We further hypothesize that changes in sleep-wake phenotypes observed in the initial hours-to-days following acute intoxication will predict the extent of cognitive and seizure outcomes (sleep as a biomarker; goal 3). Finally, we propose that early intervention with the FDA-approved dual- orexin receptor antagonist (DORA) Lemborexant will improve sleep phenotypes and protect against the development of the worst seizure and cognitive disorders while delayed intervention will reduce seizure frequency and duration and improve cognitive outcomes (sleep as a new target for intervention; goal 4). This collaborative proposal, therefore, fills a critical unmet need in the field of countermeasures research, while evaluating a potential therapeutic target and FDA-approved candidate therapy.