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

Maximilian Lenz, Marina Ben Shimon, Felix Benninger, Miri Y. Neufeld, Efrat Shavit-Stein, Andreas Vlachos*, Nicola Maggio

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: 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 may 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) may assert anti-epileptic effects in vivo. Key messages: Systemic thrombin/PAR1-inhibition ameliorates anticoagulants behavioral seizures.Status epilepticus increases thrombin levels in the hippocampus.Increased serine protease activity in the hippocampus after status epileptic.Anti-epileptic potential of clinically used anticoagulants must be evaluated.

Original languageEnglish
Pages (from-to)1567-1574
Number of pages8
JournalJournal of Molecular Medicine
Volume97
Issue number11
DOIs
StatePublished - 1 Nov 2019

Keywords

  • Blood-brain barrier
  • Hippocampus
  • Protease-activated receptor 1
  • Status epilepticus
  • Thrombin

Fingerprint

Dive into the research topics of 'Systemic thrombin inhibition ameliorates seizures in a mouse model of pilocarpine-induced status epilepticus'. Together they form a unique fingerprint.

Cite this