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

作者：Yuan Zhang, Lin Wang, Qiuling Pan, Xiaomin Yang, Yunchuan Cao, Jin Yan, Yingwen Wang, Yihao Tao, Runjin Fan, Xiaochuan Sun, Lin Li · 发表于：Fluids and Barriers of the CNS · 年份：2022 · DOI：10.1186/s12987-022-00356-6 · 被引用次数：28 · 研究领域：Barrier Structure and Function Studies、Sphingolipid Metabolism and Signaling、Cerebrospinal fluid and hydrocephalus

BACKGROUND: Traumatic brain injury (TBI) provokes secondary pathological damage, such as damage to the blood-brain 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 lymphocytopeni...