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Int J Biol Sci 2015; 11(12):1424-1435. doi:10.7150/ijbs.12930

Research Paper

Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia

Xiao Yang*,1,2, Changhun Hei*,2,3, Ping Liu2,4, Yaozu Song1, Taylor Thomas2, Sylvie Tshimanga2, Feng Wang1, Jianguo Niu1, Tao Sun1, P. Andy Li2✉

1. Neuroscience Center, General Hospital of Ningxia Medical University, Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 75004, China
2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA
3. Department of Human Anatomy, Histology and Embryology, Ningxia Medical University, Yinchuan 75004, China
4. Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
* These authors contributed equally to this work.

Abstract

The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus. Inhibition of mTOR by rapamycin markedly reduced ischemia-induced damage; suppressed p-Akt, p-mTOR, p-P70S6K and p-S6 protein levels; decreased LC3-II and Beclin-1; and prevented cytochrome c release in the two structures. All together, these data provide evidence that cerebral ischemia activates mTOR and autophagy pathways. Inhibition of mTOR deactivates the mTOR pathway, suppresses autophagy, prevents cytochrome c release and reduces ischemic brain damage.

Keywords: Autophagy, Cerebral ischemia, Cytochrome c, mTOR, Rapamycin, Reperfusion damage

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How to cite this article:
Yang X, Hei C, Liu P, Song Y, Thomas T, Tshimanga S, Wang F, Niu J, Sun T, Li PA. Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia. Int J Biol Sci 2015; 11(12):1424-1435. doi:10.7150/ijbs.12930. Available from http://www.ijbs.com/v11p1424.htm