UC Davis CounterACT Center of Excellence: Developing Therapeutic Strategies for Mitigating the Chronic Neurological Consequences of Acute Organophosphate Intoxication

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Project Summary – Overall The primary objective of the new UC Davis CounterACT Center of Excellence is to identify and develop novel therapeutic strategies that when administered as an adjunct to in-field standard of care (SOC) treatments for acute organophosphate (OP) intoxication will mitigate the onset and/or severity of long-term, adverse neurological consequences. The overarching hypothesis of the Center is that therapeutic strategies that reduce inflammation in the brain, protect blood-brain barrier (BBB) function, and/or normalize neuronal excitability will be more effective than SOC alone in improving long-term neurological outcomes. Current medical countermeasures can reduce mortality in OP-intoxicated individuals, but they do not provide protection against the long-term neurological sequelae associated with acute OP intoxication unless they are administered within minutes of exposure, which is an unlikely scenario in the event of accidental, suicidal or terrorist-related exposures. These limitations underscore the urgent need for improved medical countermeasures. The Center consists of three Research Projects: Project 1 will evaluate novel therapeutic candidates that reduce neuroinflammation; Project 2 will assess strategies for protecting BBB function; and Project 3 will test pharmacologic and electrophysiologic strategies for normalizing neuronal excitability. Three Scientific Cores support the Projects: the Analytical and Medicinal Chemistry Core will support biomarker detection, medicinal chemistry, formulation and PK studies; the Neuroimaging Core will provide preclinical in vivo and high-content imaging; and the Statistics Core will support experimental design and data analyses. A Research Education Core will provide training in countermeasure research, and an Administrative Core will function as the Center’s hub and administer the Emerging Science and Scientists Pilot Project Program. The Center will use two preclinical models of acute OP intoxication: the rat model of acute intoxication with diisopropylfluorophosphate (DFP) and the rat model of acute soman intoxication, which recapitulate the acute (cholinergic crisis and status epilepticus) and chronic (progressive neuropathology, spontaneous recurrent seizures (SRS) and cognitive impairment) effects observed in humans acutely intoxicated with OPs. Our goals in this 1st project period are to: (1) Identify novel therapeutic targets based on mechanistic studies of the pathogenesis of chronic, adverse neurological effects of acute OP intoxication. (2) Develop therapeutic candidates that when given singly or in combination as adjunct therapy to SOC prevent or mitigate chronic neurotoxicity. Therapeutic candidates include novel small molecule inhibitors of soluble epoxide hydrolase (sEH), plasminogen activator inhibitor-1 (PAI-1), or calpain; KCA channel activators; and FDA-approved therapies (IL-1β blocker, ion channel modulators and deep brain stimulation). (3) Identify biomarkers (blood-borne molecules, as well as brain electrophysiology, neuroimaging and behavioral indices) that can be translated to clinical use for predicting the development of SRS and cognitive dysfunction in exposed individuals.