AUTHOR=Ben Shimon Marina , Shavit-Stein Efrat , Altman Keren , Pick Chaim G. , Maggio Nicola 

TITLE=Thrombin as Key Mediator of Seizure Development Following Traumatic Brain Injury

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 10 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01532

DOI=10.3389/fphar.2019.01532

ISSN=1663-9812

ABSTRACT=Traumatic brain injury (TBI) commonly leads to development of seizures, accounting for approximately 20% of newly diagnosed epilepsy. Despite the high clinical significance, the mechanisms underlying the development of post traumatic seizures (PTS) remain unclear, compromising appropriate management of these patients. Accumulating evidence suggest that thrombin, the main serine protease of the coagulation cascade, is involved in PTS genesis by mediating inflammation and hyperexcitability following blood brain barrier breakdown. In order to further understand the participation of thrombin in PTS, we generated a combined mild TBI (mTBI) and epilepsy mice model, by injecting pilocarpine to mice previously submitted to head injury.  Interestingly, mTBI was able to reduce the threshold of seizure onset as well as increase the death rate in the pilocarpine treated animals. In turn, pilocarpine worsened spatial orientation of mTBI treated mice.  Finally, thrombin activity as well as the expression of IL1-β and TNF-α were significantly increased in the mTBI-pilocarpine treated animals.  In conclusion, these observations indicate a synergism between thrombin and mTBI in lowering seizure threshold and possibly aggravating inflammation. We believe that these results will improve the understanding of PTS pathophysiology and contribute to the development of more targeted therapies in the future.