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Artesunate Protected Blood–Brain Barrier via Sphingosine 1 Phosphate Receptor 1/Phosphatidylinositol 3 Kinase Pathway After Subarachnoid Hemorrhage in Rats

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Abstract

Blood–brain barrier preservation plays an important role in attenuating vasogenic brain edema after subarachnoid hemorrhage (SAH). This study was designed to investigate the protective effect and mechanism of artesunate, a traditional anti-malaria drug, on blood–brain barrier after SAH. Three hundred and seventy-seven (377) male Sprague–Dawley rats were subjected to endovascular perforation model for SAH. The rats received artesunate alone or in combination with Sphingosine-1-phosphate receptor-1 (S1P1) small interfering RNA (siRNA), antagonist VPC23019, or phosphatidylinositol 3-kinase inhibitor wortmannin after SAH. Modified Garcia score, SAH grades, brain water content, Evans blue leakage, transmission electron microscope, immunohistochemistry staining, Western blot, and cultured endothelial cells were used to investigate the optimum concentration and the therapeutic mechanism of artesunate. We found that artesunate (200 mg/kg) could do better in raising modified Garcia score, reducing brain water content and Evans blue leakage than other groups after SAH. Moreover, artesunate elevated S1P1 expression, enhanced phosphatidylinositol 3-kinase activation, lowered GSK-3β activation, stabilized β-catenin, and improved the expression of Claudin-3 and Claudin-5 after SAH in rats. These effects were eliminated by S1P1 siRNA, VPC23019, and wortmannin. This study revealed that artesunate could preserve blood–brain barrier integrity and improve neurological outcome after SAH, possibly through activating S1P1, enhancing phosphatidylinositol 3-kinase activation, stabilizing β-catenin via GSK-3β inhibition, and then effectively raising the expression of Claudin-3 and Claudin-5. Therefore, artesunate may be favorable for the blood–brain barrier (BBB) protection after SAH and become a potential candidate for the treatment of SAH patients.

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Authors and Affiliations

  1. Department of Neurosurgery, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China

    Shilun Zuo, Hongfei Ge, Qiang Li, Xuan Zhang, Rong Hu, Shengli Hu, Xin Liu, Yujie Chen & Hua Feng

  2. Department of Anesthesiology, Neurosurgery and Physiology, Loma Linda University, Loma Linda, CA, USA

    John H. Zhang

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  1. Shilun Zuo
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  2. Hongfei Ge
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Correspondence to Yujie Chen or Hua Feng.

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The authors declared that they have no competing interests.

Source of Funding

This study was funded by National Natural Science Foundation of China (No. 81501002 to Yujie Chen, No. 81220108009 to Hua Feng) and the National Basic Research Program of China (973 Program, No. 2014CB541600 to Hua Feng).

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Zuo, S., Ge, H., Li, Q. et al. Artesunate Protected Blood–Brain Barrier via Sphingosine 1 Phosphate Receptor 1/Phosphatidylinositol 3 Kinase Pathway After Subarachnoid Hemorrhage in Rats. Mol Neurobiol 54, 1213–1228 (2017). https://doi.org/10.1007/s12035-016-9732-6

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