[R01] Impaired Sleep as a Target for Intervention Following Acute Organophosphate Intoxication
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2028-07-31
Importo max: 462.117 EUR
Paese: US
Descrizione
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 an
Istituzione: UNIVERSITY OF CALIFORNIA AT DAVIS
PI: Christelle Anaclet, Gene Gabriel Gurkoff
Progetto: 5R01NS144287-02
Settori: National Institute of Neurological Disorders and Stroke
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