Back to Search Start Over

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

Authors :
Lenz M
Shimon MB
Benninger F
Neufeld MY
Shavit-Stein E
Vlachos A
Maggio N
Source :
Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2019 Nov; Vol. 97 (11), pp. 1567-1574. Date of Electronic Publication: 2019 Oct 31.
Publication Year :
2019

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.

Details

Language :
English
ISSN :
1432-1440
Volume :
97
Issue :
11
Database :
MEDLINE
Journal :
Journal of molecular medicine (Berlin, Germany)
Publication Type :
Academic Journal
Accession number :
31667526
Full Text :
https://doi.org/10.1007/s00109-019-01837-2