Brain Damage from Soman-Induced Seizures Is Greatly Exacerbated by Dimethyl sulfoxide (DMSO): Modest Neuroprotection by 2-Aminoethyl diphenylborinate (2-APB), a Transient Receptor Potential Channel Inhibitor and Inositol 1,4,5-triphosphate Receptor Antagonist

Abstract : Soman is a nerve-agent that produces seizures and seizure-related brain damage (SRBD). It is well known that termination of soman-induced seizures, using anticonvulsant drug therapy, would be the ideal means of preventing SRBD. However, these seizures quickly develop into status epilepticus and become refractory to anticonvulsant therapy shortly after their onset. Medical care for some battlefield casualties will likely be delayed beyond the therapeutic window of opportunity to terminate soman-induced seizures. Moreover, SRBD that has already been triggered will continue, along the pathological cascade, unabated by the currently fielded therapeutic regimen. Thus, there is a need for adjunct drug therapy that is capable of interrupting ensuing pathology and augmenting neuroprotection when administered, in conjunction anticonvulsants, during the refractory phase of soman-induced seizures. Considerable evidence supports a pivotal role of sustained elevations in intracellular calcium (i.e., delayed calcium overload) in SRBD resulting from soman-induced seizures and status epilepticus. In addition, there are several reports that a neuroprotective approach, aimed at attenuating delayed calcium overload, combined with standard anticonvulsant therapy, provides greater protection against soman-induced SRBD than anticonvulsant therapy alone. Transient receptor potential (TRP) channels, a new class of membrane ion channels, are responsible for capacitative calcium entry and have been linked to delayed calcium overload. The TRP channel antagonist, 2-aminoethyl diphenylborinate (2-APB), blocks calcium capacitative entry and is reported to be neuroprotective in various excitotoxic models. 2-APB is also a potent inositol 1,4,5, triphosphate (IP3) receptor antagonist and blocks release of calcium from internal stores. In the present study, we assessed the neuroprotective efficacy of 2-APB against somaninduced SRBD.