中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (8): 1763-1769.doi: 10.4103/1673-5374.360263

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

鞘氨醇-1-磷酸受体1 可调节癫痫小鼠血脑屏障的通透性

  

  • 出版日期:2023-08-15 发布日期:2023-02-23
  • 基金资助:
    国家自然科学基金项目（82071393，81830040，82130042）；广东省科技计划项目（2018B030334001）；江苏省医学优秀人才计划项目（JCRCA2016006）

Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice

Li-Xiang Yang1, Yuan-Yuan Yao2, Jiu-Rong Yang2, Hui-Lin Cheng1, *, Xin-Jian Zhu2, *, Zhi-Jun Zhang3, 4, *   

  1. 1Department of Neurosurgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China; 2Department of Pharmacology, Medical School of Southeast University, Nanjing, Jiangsu Province, China; 3Department of Neurology, Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu Province, China; 4Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
  • Online:2023-08-15 Published:2023-02-23
  • Contact: Hui-Lin Cheng, MD, chenghlzd@126.com; Xin-Jian Zhu, PhD, xinjianzhu@seu.edu.cn; Zhi-Jun Zhang, PhD, janemengzhang@vip.163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82071393 (to HLC), 81830040 (to ZJZ), 82130042 (to ZJZ); Science and Technology Program of Guangdong Province, No. 2018B030334001 (to ZJZ); and the Program of Excellent Talents in Medical Science of Jiangsu Province, No. JCRCA2016006 (to ZJZ).

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摘要：

血脑屏障破坏被认为是癫痫发展的关键。多项研究表明鞘氨醇-1-磷酸受体1参与调节血管完整性，但其是否能影响癫痫后血脑屏障通透性目前仍不清楚。实验以毛果芸香碱诱导的癫痫持续状态C57BL/6 小鼠模型，继而以戊四唑点燃癫痫，可见癫痫发作后的海马中鞘氨醇-1-磷酸受体1表达增加，而紧密连接蛋白表达降低。而腹腔注射鞘氨醇-1-磷酸受体1特异性激动剂SEW2871可降低癫痫小鼠海马中紧密连接蛋白水平，增加血脑屏障渗漏，并加重癫痫发作的严重程度；而鞘氨醇-1-磷酸受体1特异性拮抗剂W146则可提高紧密连接蛋白水平，减轻血脑屏障破坏，并降低癫痫发作的严重程度。此外，鞘氨醇-1-磷酸受体1还可促进白细胞介素1β和肿瘤坏死因子α的分泌以及星形胶质细胞活化。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可被神经炎症抑制剂米诺环素逆转。行为学实验显示鞘氨醇-1-磷酸受体1可加重癫痫相关的抑郁样行为。最后，特异性敲低星形胶质细胞鞘氨醇-1-磷酸受体1可抑制神经炎症反应，减轻血脑屏障渗漏、癫痫发作严重程度和癫痫相关的抑郁样行为。综上表明，鞘氨醇-1-磷酸受体1可通过促进神经炎症加剧癫痫海马中血脑屏障的破坏。

https://orcid.org/0000-0002-9107-6179 (Hui-Lin Cheng); https://0000-0001-8386-4952 (Xin-Jian Zhu); https://0000-0001-5480-0888 (Zhi-Jun Zhang)

关键词: 鞘氨醇-1-磷酸受体1, 神经炎症, 紧密连接, 血脑屏障, 星形胶质细胞, 毛果芸香碱, 戊四唑, 癫痫, 癫痫相关的抑郁样行为, 腺相关病毒

Abstract: 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. 

Key words: adeno-associated virus, astrocytes, blood-brain barrier, epilepsy, epilepsy-associated depression-like behavior, neuroinflammation, pentylenetetrazol, pilocarpine, tight junction