Novel Anticonvulsant and Neuroprotective Therapies for TETS and OP Intoxication

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The primary objective of the UC Davis CounterACT Center of Excellence is to identify and advance improved medical countermeasures for rapidly terminating seizures and mitigating the delayed neurologic consequences following acute intoxication with convulsant chemical threat agents. The Center comprises three research projects: Project 1 discovers therapeutic candidates via in vitro mechanistic screens, which are tested for in vivo antiseizure and neuroprotective efficacy by Projects 2 and 3, respectively. The projects rely on three scientific cores to support drug analysis and biomarker detection (Core A), medicinal chemistry and pharmacological testing (Core B), and experimental design and data analysis (Core C). A Research Education Core supports training in countermeasure research, and an Administrative Core oversees and coordinates scientific and administrative operations. The Center focuses on the GABAA receptor antagonist tetramethylenedisulfotetramine (TETS) and the organophosphate cholinesterase inhibitor diisopropylfluorophosphate (DFP), which can trigger convulsions that progress to life threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including mild-to-severe memory loss, affective disorders and recurrent seizures. Current medical countermeasures can reduce mortality in exposed individuals, but they do so with significant side effects and are maximally effective only if administered within minutes of exposure. These limitations underscore the urgent need for improved medical countermeasures. In the first project period, we developed innovative in vitro platforms for mechanism-based screening to identify candidate antiseizure and neuroprotective therapeutics, and novel preclinical models that recapitulate acute seizure activity and neurological deficits observed in humans following acute intoxication with TETS or OPs. Using these models, we discovered: (1) allopregnanolone, a GABAA receptor positive allosteric modulator, was a superior countermeasure for TETS-induced SE, and (2) combining standard-of-care with allopregnanolone and a low dose of perampanel, a potent AMPA receptor antagonist, was more effective than standard-of-care alone in terminating DFP-induced SE. We also discovered that neuropathology was mitigated by post-exposure treatment with dantrolene, a Ca2+ channel stabilizer, or a novel small molecule dual inhibitor of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2). Our goals in this second project period are to: (1) advance our antiseizure lead allopregnanolone; (2) continue development of allopregnanolone and perampanel; (3) identify adjunct neuroprotective leads, focusing initially on the dual sEH-COX-2 inhibitor and dantrolene; and (4) conduct mechanistic studies to discover new therapeutic candidates. Our milestones for the second project period are to: (i) produce data and a regulatory strategy to advance allopregnanolone for treatment of GABAAR antagonist-induced seizures; (ii) determine whether combination treatment with allopregnanolone and perampanel warrants development as a lead “universal antidote”; and (iii) identify lead neuroprotective treatments for improving long-term outcomes.