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

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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.

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Funding

The work was supported by German Israeli Foundation (GIF G-1317-418.13/2015 to AV and NM).

Author information

Author notes

  1. Andreas Vlachos and Nicola Maggio are joint senior authors.

Authors and Affiliations

  1. Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany

    Maximilian Lenz & Andreas Vlachos

  2. Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel

    Marina Ben Shimon, Miri Y. Neufeld, Efrat Shavit-Stein & Nicola Maggio

  3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Marina Ben Shimon, Felix Benninger, Miri Y. Neufeld, Efrat Shavit-Stein & Nicola Maggio

  4. Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel

    Felix Benninger

  5. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Felix Benninger

  6. Center for Basics in Neuromodulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany

    Andreas Vlachos

  7. Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Tel HaShomer, Israel

    Nicola Maggio

  8. Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Nicola Maggio

  9. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Nicola Maggio

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  1. Maximilian Lenz
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Correspondence to Andreas Vlachos or Nicola Maggio.

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Animal handling was approved by the Institutional Animal Care and Use Committee at the Chaim Sheba Medical Center, which adheres to the national law and NIH rules (registration no.: 736/12).

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The authors declare that there are no competing interests.

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Maximilian Lenz and Marina Ben Shimon are joint first authors.

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Lenz, M., Shimon, M.B., Benninger, F. et al. Systemic thrombin inhibition ameliorates seizures in a mouse model of pilocarpine-induced status epilepticus. J Mol Med 97, 1567–1574 (2019). https://doi.org/10.1007/s00109-019-01837-2

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  • DOI: https://doi.org/10.1007/s00109-019-01837-2

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