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Abstract
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 (Ca 2+
) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression
of neurological morbidities associated with OP-SE survival. We have observed development
of a “Ca 2+ plateau” characterized by sustained elevations in neuronal Ca 2+ levels
in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities.
These Ca 2+ elevations had their origin in Ca 2+ release from the intracellular
stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam
lowered OP-SE mediated Ca 2+ plateau and afforded significant neuroprotection. Since
the Ca 2+ 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 Ca 2+ mediated OP-SE neuropsychiatric comorbidities
such as depression, anxiety, and acquired epilepsy (AE).