破坏血脑屏障是癫痫病理学的关键组成部分。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，它对癫痫小鼠的血脑屏障渗透性的影响仍不清楚。在本研究中，我们在C57BL / 6小鼠中准备了吡咯烷诱导的状态性癫痫模型和五氮杂三唑诱导的癫痫模型。状态性癫痫后，海马中的S1P1表达增加，而紧密连接蛋白的表达在癫痫小鼠中与对照组相比减少。腹腔注射S1P1特异性激动剂SEW2871，降低了癫痫小鼠海马中的紧密连接蛋白水平，增加了血脑屏障泄漏，并且与对照组相比加重了癫痫发作的严重程度。特异性拮抗剂W146增加了紧密连接蛋白的水平，减轻了血脑屏障破坏，并与对照组相比降低了癫痫发作的严重程度。此外，鞘氨醇1-磷酸受体1促进了白细胞介素-1β和肿瘤坏死因子-α的产生，并引起星形胶质细胞增生。使用神经炎症抑制剂微孔膜素可逆转鞘氨醇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加重了与癫痫有关的抑郁症状。此外，星形胶质细胞S1P1的特异性敲低抑制了神经炎症反应，减轻了血脑屏障泄漏，癫痫发作的严重程度和与癫痫有关的抑郁症状。综上所述，我们的研究结果表明，星形胶质细胞中的鞘氨醇1-磷酸受体1通过促进神经炎症加剧了癫痫大脑的血脑屏障破坏。

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.