Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel.
J Mol Med (Berl). 2019 Nov;97(11):1567-1574. doi: 10.1007/s00109-019-01837-2. Epub 2019 Oct 31.
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.
癫痫持续状态（SE）是一种危及生命的疾病，其特征是持续的癫痫发作，如果得不到适当的治疗，可能会导致严重的脑损伤和死亡。最近的研究表明，血脑屏障（BBB）功能的改变以及随后皮质暴露于凝血因子可能启动、促进和/或维持 SE。这一观点是基于这样的观察结果，即丝氨酸蛋白酶凝血酶在凝血级联反应中起着至关重要的作用，通过激活蛋白酶激活受体 1（PAR1）增加神经兴奋性。然而，目前尚不清楚全身抑制凝血酶是否在体内具有“抗癫痫”作用。我们在这里使用成年 3 个月大雄性小鼠的匹罗卡品 SE 模型来解决以下问题：腹腔注射凝血酶抑制剂 α-NAPAP（0.75mg/kg）是否能对抗 SE。事实上，凝血酶的药理学抑制可改善匹罗卡品诱导的 SE 的行为结果。当在 SE 诱导前通过腹腔注射 SCH79797（25μg/kg）药理学阻断凝血酶受体 PAR1 时，也会得到类似的结果。与这些结果一致的是，在匹罗卡品处理的动物的海马体中检测到凝血酶免疫荧光增加。此外，在 SE 诱导后 90 分钟检测到海马丝氨酸蛋白酶活性增加，而在 SE 诱导前用 α-NAPAP 处理的动物中未观察到这种情况。综上所述，这些结果证实并扩展了最近的研究，表明针对凝血酶（和 PAR1）的新型口服抗凝剂可能在体内具有抗癫痫作用。 关键信息：全身凝血酶/PAR1 抑制可改善抗凝剂引起的癫痫发作。癫痫持续状态增加海马体中的凝血酶水平。癫痫持续状态后海马体中丝氨酸蛋白酶活性增加。必须评估临床使用的抗凝剂的抗癫痫潜力。
