Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1β and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy-associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.

中文翻译：

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鞘氨醇 1-磷酸受体 1 调节癫痫小鼠的血脑屏障通透性。

血脑屏障的破坏是癫痫病理学的一个重要组成部分。多项研究表明，鞘氨醇 1-磷酸受体 1 有助于调节血管完整性。然而，其对癫痫小鼠血脑屏障通透性的影响仍不清楚。在这项研究中，我们在 C57BL/6 小鼠中制备了毛果芸香碱诱导的癫痫持续状态模型和戊四唑诱导的癫痫模型。癫痫持续状态后海马体中 S1P1 表达增加，而与对照组相比，癫痫小鼠的紧密连接蛋白表达降低。腹腔注射鞘氨醇-1-磷酸受体 1 特异性激动剂 SEW2871 可降低癫痫小鼠海马紧密连接蛋白水平，增加血脑屏障渗漏，并且与对照组相比加重了癫痫发作的严重程度。W146 是鞘氨醇-1-磷酸受体 1 的特异性拮抗剂，与对照组相比，它增加了紧密连接蛋白的水平，减轻了血脑屏障的破坏，并降低了癫痫发作的严重程度。此外，鞘氨醇1-磷酸受体1促进白细胞介素-1β和肿瘤坏死因子-α的产生并引起星形细胞增多。神经炎症抑制剂米诺环素可逆转鞘氨醇 1-磷酸受体 1 对紧密连接蛋白和血脑屏障完整性的破坏。行为测试显示鞘氨醇 1-磷酸受体 1 加剧了癫痫相关的抑郁样行为。此外，星形胶质细胞 S1P1 的特异性敲低抑制了神经炎症反应并减弱了血脑屏障渗漏，癫痫发作的严重程度和癫痫相关的抑郁样行为。综上所述，我们的结果表明，星形胶质细胞鞘氨醇 1-磷酸受体 1 通过促进神经炎症，加剧了癫痫脑中的血脑屏障破坏。