Int J Med Sci 2021; 18(2):304-313. doi:10.7150/ijms.49066

Research Paper

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury

Hao Cheng1*, Guangfu Di1*, Chao-Chao Gao2*, Guoyuan He1, Xue Wang3, Yan-Ling Han3, Le-an Sun1, Meng-Liang Zhou3✉, Xiaochun Jiang1✉

1. Department of Neurosurgery, Yijishan Hospital, Wannan Medical College, Anhui, China.
2. Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Jiangsu, China.
3. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Jiangsu, China.
*These authors contributed equally to this work.

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Citation:
Cheng H, Di G, Gao CC, He G, Wang X, Han YL, Sun La, Zhou ML, Jiang X. FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury. Int J Med Sci 2021; 18(2):304-313. doi:10.7150/ijms.49066. Available from https://www.medsci.org/v18p0304.htm

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Abstract

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. A sequence of pathological processes occurred when there is TBI. Previous studies showed that sphingosine-1-phosphate receptor 1 (S1PR1) played a critical role in inflammatory response in the brain after TBI. Thus, the present study was designed to evaluate the effects of the S1PR1 modulator FTY720 on neurovascular unit (NVU) after experimental TBI in mice. The weight-drop TBI method was used to induce TBI. Western blot (WB) was performed to determine the levels of SIPR1, claudin-5 and occludin at different time points. FTY720 was intraperitoneally administered to mice after TBI was induced. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess endothelial cell apoptosis. Immunofluorescence and WB were performed to measure the expression of tight junction proteins: claudin-5 and occludin. Evans blue (EB) permeability assay and brain water content were applied to evaluate the blood-brain barrier (BBB) permeability and brain edema. Immunohistochemistry was performed to assess the activation of astrocytes and microglia. The results showed that FTY720 administration reduced endothelial cell apoptosis and improved BBB permeability. FTY720 also attenuated astrocytes and microglia activation. Furthermore, treatment with FTY720 not only improved neurological function, but also increased the survival rate of mice significantly. These findings suggest that FTY720 administration restored the structure of the NVU after experimental TBI by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes. Moreover, FTY720 might reduce inflammation in the brain by reducing the activation of microglia in TBI mice.

Keywords: FTY720, sphingosine-1-phosphate receptor 1, traumatic brain injury, blood-brain barrier, endothelial cell