Selective sphingosine-1-phosphate receptor 1 modulator attenuates blood-brain barrier disruption following traumatic brain injury by inhibiting vesicular transcytosis

作者全名："Zhang, Yuan; Wang, Lin; Pan, Qiuling; Yang, Xiaomin; Cao, Yunchuan; Yan, Jin; Wang, Yingwen; Tao, Yihao; Fan, Runjin; Sun, Xiaochuan; Li, Lin"

作者地址："[Zhang, Yuan; Wang, Lin; Pan, Qiuling; Yang, Xiaomin; Cao, Yunchuan; Yan, Jin; Wang, Yingwen; Sun, Xiaochuan; Li, Lin] Chongqing Med Univ, Dept Neurosurg, Neural Injury & Protect Lab, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zhang, Yuan; Wang, Lin; Fan, Runjin] North Sichuan Med Coll, Nanchong Cent Hosp, Dept Neurosurg, Clin Med Coll 2, Nanchong, Peoples R China; [Tao, Yihao] Chongqing Med Univ, Nanchong Cent Hosp, Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Sun, XC; Li, L (通讯作者)，Chongqing Med Univ, Dept Neurosurg, Neural Injury & Protect Lab, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：FLUIDS AND BARRIERS OF THE CNS

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000973481300001

JCR分区：Q1

影响因子：7.3

年份：2022

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Traumatic brain injury; Blood-brain barrier; Vesicular transcytosis; Mfsd2a; S1P1 modulator

摘要："Background: Traumatic brain injury ( TBI) provokes secondary pathological damage, such as damage to the bloodbrain barrier (BBB), ischaemia and inflammation. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be critical in limiting the increase in BBB vesicle transcytosis following brain injury. Recent studies suggest that a novel and selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1), CYM-5442, maintains the integrity of the BBB by restricting vesicle transcytosis during acute ischaemic stroke. In the current study, we investigated whether CYM-5442, evaluated in a short-term study, could protect the brains of mice with acute-stage TBI by reversing the increase in vesicle transport due to reduced Mfsd2a expression after TBI. Methods: We used the well-characterized model of TBI caused by controlled cortical impact. CYM-5442 (0.3, 1, 3 mg/ kg) was intraperitoneally injected 30 min after surgery for 7 consecutive days. To investigate the effect of CYM-5442 on vesicle transcytosis, we downregulated and upregulated Mfsd2a expression using a specific AAV prior to evaluation of the TBI model. MRI scanning, cerebral blood flow, circulating blood counts, ELISA, TEM, WB, and immunostaining evaluations were performed after brain injury. Results: CYM-5442 significantly attenuated neurological deficits and reduced brain oedema in TBI mice. CYM-5442 transiently suppressed lymphocyte trafficking but did not induce persistent lymphocytopenia. After TBI, the levels of Mfsd2a were decreased significantly, while the levels of CAV-1 and albumin were increased. In addition, Mfsd2a deficiency caused inadequate sphingosine-1-phosphate (S1P) transport in the brain parenchyma, and the regulation of BBB permeability by Mfsd2a after TBI was shown to be related to changes in vesicle transcytosis. Downregulation of Mfsd2a in mice markedly increased the BBB permeability, neurological deficit scores, and brain water contents after TBI. Intervention with CYM-5442 after TBI protected the BBB by significantly reducing the vesicle transcytosis of cerebrovascular endothelial cells. Conclusion: In addition to transiently suppressing lymphocytes, CYM-5442 alleviated the neurological deficits, cerebral edema and protective BBB permeability in TBI mice by reducing the vesicle transcytosis of cerebrovascular endothelial cells."

基金机构：National Natural Science Foundation of China [82071397]; Chongqing Natural Science Foundation [cstc2020jcyj-msxmX0225]

基金资助正文：This work was supported by grants from the National Natural Science Foundation of China (Grant number 82071397) and Chongqing Natural Science Foundation (Grant No. cstc2020jcyj-msxmX0225).