Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (8): 1763-1769.doi: 10.4103/1673-5374.360263

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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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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