Novel therapeutics for treating organophosphate-induced status epilepticus co-morbidities, based on changes in...

Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP exposure is associated with a cholinergic crisis and status epilepticus (SE). It is also known that the survivors of OP toxicity exhibit neurobehavioral deficits such as mood changes, depression, and memory impairment, and acquired epilepsy. Our research has focused on addressing the need to develop effective therapeutic agents that could be administered even after prolonged seizures and would prevent or lessen the chronic morbidity associated with OP-SE survival. We have developed rat survival models of OP pesticide metabolite paraoxon (POX) and nerve agent sarin surrogate diisopropyl fluorophosphate (DFP) induced SE that are being used to screen for medical countermeasures against an OP attack. Our research has focused on studying neuronal calcium (Ca²⁺) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a "Ca²⁺ plateau" characterized by sustained elevations in neuronal Ca²⁺ levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca²⁺ elevations had their origin in Ca²⁺ release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca²⁺ plateau and afforded significant neuroprotection. Since the Ca²⁺ plateau lasts for a prolonged period, our studies suggest that blocking it after the control of SE may represent a unique target for development of novel countermeasures to prevent long term Ca²⁺ mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).