systemic thrombin inhibition ameliorates seizures in a mouse model of pilocarpine-induced status epilepticus

Status epilepticus (se) is a life-threatening condition characterized by ongoing seizure activity which can lead to severe brain damage and death if not treated properly. recent work suggests that alterations in blood-brain barrier (bbb) function and subsequent cortical exposure to coagulation factors initiate, promote, and/or sustain se. this suggestion is based on the observation that the serine protease thrombin, which plays a fundamental role in the blood coagulation cascade, increases neural excitability through the activation of protease-activated receptor 1 (par1). however, it remains unclear whether systemic inhibition of thrombin asserts “anti-epileptic” effects in vivo. we here used the pilocarpine model of se in adult 3-month-old male mice to address the question whether intraperitoneal injection of the thrombin inhibitor α-napap (0.75 mg/kg) counters se. indeed, pharmacological inhibition of thrombin ameliorates the behavioral outcome of pilocarpine-induced se. similar results are obtained when the thrombin receptor par1 is pharmacologically blocked using intraperitoneal injection of sch79797 (25 μg/kg) prior to se induction. consistent with these results, an increase in thrombin immunofluorescence is detected in the hippocampus of pilocarpine-treated animals. moreover, increased hippocampal serine protease activity is detected 90 min after se induction, which is not observed in animals treated with α-napap prior to se induction. together, these results corroborate and extend recent studies suggesting that novel oral anticoagulants which target thrombin (and par1) assert anti-epileptic effects in vivo.