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Int J Biol Sci 2017; 13(7):878-887. doi:10.7150/ijbs.18976

Research Paper

Inhibition of mTOR signaling Confers Protection against Cerebral Ischemic Injury in Acute Hyperglycemic Rats

Changchun Hei1, 2*, Ping Liu3, 2*, Xiao Yang2, 4, Jianguo Niu1, P. Andy Li2✉

1. Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region and Department Human Anatomy, Histology and Embryology, Ningxia Medical University, Yinchuan 750004, 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 Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China;
4. Neuroscience Center, General Hospital of Ningxia Medical University, and Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 750004, China.
* These two authors contributed equally to this work.

Abstract

Hyperglycemia is known to exacerbate neuronal death resulted from cerebral ischemia. The mechanisms are not fully understood. The mammalian target of rapamycin (mTOR) pathway regulates cell growth, division and apoptosis. Recent studies suggest that activation of mTOR may mediate ischemic brain damage. The objective of the present experiment is to explore whether mTOR mediates ischemic brain damage in acute hyperglycemic animals. Rats were subjected to 10 min of forebrain ischemia under euglycemic, hyperglycemic and rapamycin-treated hyperglycemic conditions. The rat brain samples were collected from the cortex and hippocampi after 3h and 16h of reperfusion. The results showed that hyperglycemia significantly increased neuronal death in the cortex and hippocampus and the exacerbation effect of hyperglycemia was associated with further activation of mTOR under control and/or ischemic conditions. Inhibition of mTOR with rapamycin ameliorated the damage and suppressed hyperglycemia-elevated p-MTOR, p-P70S6K and p-S6. In addition, hyperglycemia per se increased the levels of cytosolic cytochrome c and autophagy marker LC3-II, while rapamycin alleviated these alterations. It is concluded that activation of mTOR signaling may play a detrimental role in mediating the aggravating effect of hyperglycemia on cerebral ischemia.

Keywords: Cerebral ischemia, Hyperglycemia, mTOR, Pathology, Rapamycin, Rat.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Hei C, Liu P, Yang X, Niu J, Li PA. Inhibition of mTOR signaling Confers Protection against Cerebral Ischemic Injury in Acute Hyperglycemic Rats. Int J Biol Sci 2017; 13(7):878-887. doi:10.7150/ijbs.18976. Available from http://www.ijbs.com/v13p0878.htm