Shavit-Stein Efrat, Berkowitz Shani, Davidy Tal, Fennig Uri, Gofrit Shani Guly, Dori Amir, Maggio Nicola
Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, Israel.
Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Front Cell Neurosci. 2022 May 24;16:900925. doi: 10.3389/fncel.2022.900925. eCollection 2022.
Status epilepticus (SE) leads to memory impairment following a seizure, attributed to long-term potentiation (LTP) reduction. Thrombin, a coagulation factor that activates protease-activated receptor 1 (PAR1) is involved in cognitive impairment following traumatic brain injury by reducing hippocampal LTP and in seizures as seen in a SE pilocarpine-induced mice model. Thrombin pathway inhibition prevents this cognitive impairment. We evaluated the effect of thrombin pathway inhibition in the pilocarpine-induced SE mice model, on LTP, hippocampal, and serum markers for inflammation, the PAR1 pathway, and neuronal cell damage.
SE was induced by injecting C57BL/6J mice with pilocarpine. Before pilocarpine injection, mice were injected with either the specific thrombin inhibitor α-NAPAP [Nα-(2-naphthalene-sulfonylglycyl)-4-amidino-DL-phenylalaninepiperidide], the PAR1 antagonist SCH79797, or vehicle-only solution. Recordings of excitatory postsynaptic potentials (EPSP) were conducted from hippocampal slices 24 h following pilocarpine injection. Hippocampal real-time PCR for the quantification of the PAR1, prothrombin, and tumor necrosis factor α (TNF-α) mRNA expression levels was conducted. Serum levels of neurofilament light chain (NfL) and TNF-α were measured by a single molecule array assay.
The EPSP was reduced in the pilocarpine-induced SE mice ( < 0.001). This reduction was prevented by both NAPAP and SCH79797 treatments ( < 0.001 for both treatments). Hippocampal expression of TNF-α was elevated in the pilocarpine-induced SE group compared to the control ( < 0.01), however, serum levels of TNF-α were not changed. NfL levels were elevated in the pilocarpine-induced SE group ( = 0.04) but not in the treated groups.
Pilocarpine-induced SE reduces LTP, in a thrombin PAR1-related mechanism. Elevation of serum NfL supports neuronal damage accompanying this functional abnormality which may be prevented by PAR1 pathway modulation.
癫痫持续状态（SE）发作后会导致记忆障碍，这归因于长时程增强（LTP）降低。凝血酶是一种激活蛋白酶激活受体1（PAR1）的凝血因子，通过降低海马LTP参与创伤性脑损伤后的认知障碍，并在毛果芸香碱诱导的SE小鼠模型中参与癫痫发作。凝血酶途径抑制可预防这种认知障碍。我们评估了在毛果芸香碱诱导的SE小鼠模型中，凝血酶途径抑制对LTP、海马以及炎症、PAR1途径和神经元细胞损伤的血清标志物的影响。
通过向C57BL/6J小鼠注射毛果芸香碱诱导SE。在注射毛果芸香碱之前，给小鼠注射特异性凝血酶抑制剂α-NAPAP [Nα-(2-萘磺酰甘氨酰)-4-脒基-DL-苯丙氨酸哌啶]、PAR1拮抗剂SCH79797或仅注射溶剂。在注射毛果芸香碱24小时后，从海马切片记录兴奋性突触后电位（EPSP）。进行海马实时PCR以定量PAR1、凝血酶原和肿瘤坏死因子α（TNF-α）的mRNA表达水平。通过单分子阵列测定法测量血清神经丝轻链（NfL）和TNF-α水平。
毛果芸香碱诱导的SE小鼠的EPSP降低（<0.001）。NAPAP和SCH79797处理均能预防这种降低（两种处理均<0.001）。与对照组相比，毛果芸香碱诱导的SE组中TNF-α的海马表达升高（<0.01），然而，血清TNF-α水平没有变化。毛果芸香碱诱导的SE组中NfL水平升高（=0.04），但在处理组中未升高。
毛果芸香碱诱导的SE通过凝血酶PAR1相关机制降低LTP。血清NfL升高支持伴随这种功能异常的神经元损伤，PAR1途径调节可能预防这种损伤。
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