Thrombin and the Protease-Activated Receptor-1 in Organophosphate-Induced Status Epilepticus.

Abstract

Organophosphates (OP) are a major threat to the health of soldiers and civilians due to their use as chemical weapons in war and in terror attacks. Among the acute manifestations of OP poisoning, status epilepticus (SE) is bearing the highest potential for long-term damages. Current therapies do not prevent brain damage and seizure-related brain injuries in OP-exposed humans. Thrombin is a serine protease known to have a fundamental function in the clotting cascade. It is highly expressed in the brain where we have previously found that it regulates synaptic transmission and plasticity. In addition, we have found that an excess of thrombin in the brain leads to hyperexcitability and therefore seizures through a glutamate-dependent mechanism. In the current study, we carried out in vitro, ex vivo, and in vivo experiments in order to determine the role of thrombin and its receptor PAR-1 in paraoxon-induced SE. Elevated thrombin activity was found in the brain slices from mice that were treated (in vitro and in vivo) with paraoxon. Increased levels of PAR-1 and pERK proteins and decreased prothrombin mRNA were found in the brains of paraoxon-treated mice. Furthermore, ex vivo and in vivo electrophysiological experiments showed that exposure to paraoxon causes elevated electrical activity in CA1 and CA3 regions of the hippocampus. Moreover, a specific PAR-1 antagonist (SCH79797) reduced this activity. Altogether, these results reveal the importance of thrombin and PAR-1 in paraoxon poisoning. In addition, the results indicate that thrombin and PAR-1 may be a possible target for the treatment of paraoxon-induced status epilepticus.