Sphingosine 1-phosphate receptor 1 regulates bloodbrain barrier permeability in epileptic mice  

作　　者：Li-Xiang Yang Yuan-Yuan Yao Jiu-Rong Yang Hui-Lin Cheng Xin-Jian Zhu Zhi-Jun Zhang 

机构地区：[1]Department of Neurosurgery,Zhongda Hospital,School of Medicine,Southeast University,Nanjing,Jiangsu Province,China [2]Department of Pharmacology,Medical School of Southeast University,Nanjing,Jiangsu Province,China [3]Department of Neurology,Zhongda Hospital,School of Medicine,Institution of Neuropsychiatry,Key Laboratory of Developmental Genes and Human Disease,Southeast University,Nanjing,Jiangsu Province,China [4]Department 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

出　　处：《Neural Regeneration Research》2023年第8期1763-1769,共7页中国神经再生研究（英文版）

基　　金：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);the Program of Excellent Talents in Medical Science of Jiangsu Province,No.JCRCA2016006(to ZJZ)。

摘　　要：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-1βand tumor necrosis factor-αand 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.

关 键 词：adeno-associated virus ASTROCYTES blood-brain barrier EPILEPSY epilepsy-associated depression-like behavior NEUROINFLAMMATION PENTYLENETETRAZOL PILOCARPINE tight junction 

分 类 号：R741[医药卫生—神经病学与精神病学]