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Traumatic Brain Injury-Induced Neuronal Apoptosis is Reduced Through Modulation of PI3K and Autophagy Pathways in Mouse by FTY720

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Abstract

FTY720 is a synthetic compound produced by modification of metabolite from Isaria sinclairii. It is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues, thereby causing peripheral lymphopenia. Growing evidences have suggested that apoptosis and autophagy were involved in the secondary brain injury after traumatic brain injury (TBI) although FTY720 exerted neuroprotective effects in a variety of neurological diseases except TBI. The present study was aimed to investigate the role of FTY720 in a mouse model of TBI. In experiment 1, ICR mice were divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + FTY720 group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 administration after TBI improved neurobehavioral function, alleviated brain edema, accompanied by modulation of apoptotic indicators such as Bcl-2, Bcl-xL, Bax, and cytochrome c. In experiment 2, ICR mice were also divided into four groups: sham group, TBI + vehicle group, TBI + FTY720 group, and TBI + FTY720 + inhibitors group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 increased the expression of phospho-protein kinase B (AKT) and some autophagy markers such as LC3 and Beclin 1. In addition, the apoptosis inhibition effect of FTY720 was partly abrogated by the phosphatidylinositide 3-kinases (PI3K)/AKT pathway inhibitor LY294002 and autophagy inhibitor 3-methyladenine. Collectively, our data provide the first evidence that FTY720 exerted neuroprotective effects after TBI, at least in part, through the activation of PI3K/AKT pathway and autophagy.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81371357 & 81401026) and the China Postdoctoral Science Foundation funded project under Grant (No. 2014M562665).

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The authors declare no potential conflicts of interest.

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    Authors and Affiliations

    1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China

      Li Zhang, Ke Ding, Handong Wang, Yong Wu & Jianguo Xu

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    1. Li Zhang
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    2. Ke Ding
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    3. Handong Wang
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    Correspondence to Handong Wang.

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    Li Zhang and Ke Ding equally contributed to this work.

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    Zhang, L., Ding, K., Wang, H. et al. Traumatic Brain Injury-Induced Neuronal Apoptosis is Reduced Through Modulation of PI3K and Autophagy Pathways in Mouse by FTY720. Cell Mol Neurobiol 36, 131–142 (2016). https://doi.org/10.1007/s10571-015-0227-1

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