Thrombin and the Protease-Activated Receptor-1 in Organophosphate-Induced Status Epilepticus
Thrombin and the Protease-Activated Receptor-1 in Organophosphate-Induced Status Epilepticus
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DOI：
10.1007/s12031-018-1228-6
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发表时间：
2019-02-01
影响因子：
3.1
通讯作者：
Maggio, Nicola
中科院分区：
文献类型：
--
作者：
Golderman, Valery;Shavit-Stein, Efrat;Maggio, Nicola
有机磷酸盐（OP）是对士兵和平民健康的主要威胁，因为它们在战争和恐怖袭击中被用作化学武器。在OP中毒的急性表现中，癫痫持续状态（SE）具有最高的长期损害潜力。目前的治疗不能预防OP暴露人群的脑损伤和脑损伤相关的脑损伤。凝血酶是已知在凝血级联中具有基本功能的丝氨酸蛋白酶。它在大脑中高度表达，我们以前发现它调节突触传递和可塑性。此外，我们还发现，大脑中过量的凝血酶会导致过度兴奋，从而通过谷氨酸依赖性机制导致癫痫发作。在目前的研究中，我们进行了在体外，离体和体内实验，以确定凝血酶及其受体PAR-1在对氧磷诱导的SE的作用。在用对氧磷处理（体外和体内）的小鼠脑切片中发现凝血酶活性升高。PAR-1和pERK蛋白水平的增加和凝血酶原mRNA的减少被发现在对氧磷处理的小鼠的脑中。此外，离体和体内电生理实验表明，暴露于对氧磷导致海马CA 1和CA 3区的电活动升高。此外，一个特定的PAR-1拮抗剂（SCH 79797）减少这种活动。总之，这些结果揭示了凝血酶和PAR-1在对氧磷中毒中的重要性。此外，结果表明凝血酶和PAR-1可能是治疗对氧磷诱导的癫痫持续状态的可能靶点。
Organophosphates (OP) are a major threat to the health of soldiers and civilians due to their use as chemical weapons in war and in terror attacks. Among the acute manifestations of OP poisoning, status epilepticus (SE) is bearing the highest potential for long-term damages. Current therapies do not prevent brain damage and seizure-related brain injuries in OP-exposed humans. Thrombin is a serine protease known to have a fundamental function in the clotting cascade. It is highly expressed in the brain where we have previously found that it regulates synaptic transmission and plasticity. In addition, we have found that an excess of thrombin in the brain leads to hyperexcitability and therefore seizures through a glutamate-dependent mechanism. In the current study, we carried out in vitro, ex vivo, and in vivo experiments in order to determine the role of thrombin and its receptor PAR-1 in paraoxon-induced SE. Elevated thrombin activity was found in the brain slices from mice that were treated (in vitro and in vivo) with paraoxon. Increased levels of PAR-1 and pERK proteins and decreased prothrombin mRNA were found in the brains of paraoxon-treated mice. Furthermore, ex vivo and in vivo electrophysiological experiments showed that exposure to paraoxon causes elevated electrical activity in CA1 and CA3 regions of the hippocampus. Moreover, a specific PAR-1 antagonist (SCH79797) reduced this activity. Altogether, these results reveal the importance of thrombin and PAR-1 in paraoxon poisoning. In addition, the results indicate that thrombin and PAR-1 may be a possible target for the treatment of paraoxon-induced status epilepticus.