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Journal of Chinese Pharmaceutical Sciences ›› 2016, Vol. 25 ›› Issue (8): 598-604.DOI: 10.5246/jcps.2016.08.067

• Original articles • Previous Articles     Next Articles

002C-3 protects the brain against ischemia-reperfusion injury by inhibiting autophagy and stimulating CaMKK/CaMKIV/HDAC4 pathways in mice

Jingliang Zhang1#, Tao Hu1#, Xiaoyan Liu1, Yuanjun Zhu1, Xiaoling Chen1, Ye Liu2, Yinye Wang1*   

  1. 1. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
    2. Beijing Honghui New Medical Technology Co.Ltd., Beijing Daxing Biological Medicine Industry Base, Beijing 102600,China
  • Received:2016-02-27 Revised:2016-04-15 Online:2016-09-01 Published:2016-05-10
  • Contact: Tel.: +86-010-82802652/+86-010-62015584, E-mail: wangyinye@bjmu.edu.cn
  • Supported by:
    National Natural Science Foundation of China (Grant No. 81302763, 81573333) and Beijing Natural Science Foundation (Grant No. 7144218).

Abstract:

This study was designed to investigate the effect of 002C-3, a derivative of magnolol, on transient cerebral middle occlusion (tMCAO) in a mice model and to identify the underlying mechanisms. 002C-3 (100 and 150 μg/kg, i.v. after ending occlusion) significantly reduced neurological deficit scores, infarct volumes, and brain water contents after 1.5 h MCAO and 24 h reperfusion. 002C-3 (75-150 µg/kg) decreased the exudation of Evans blue from brain capillaries. 002C-3 (100 μg/kg) significantly inhibited the activity of MMP-9 and MMP-2 in the injured hemisphere. 002C-3 decreased the expression of autophagy-associated proteins, Beclin-1 and LC3B-II, and increased the level of p62 in injured hemisphere. 002C-3 (100 μg/kg) significantly increased the expression of p-CaMKIV and p-HDAC4 in injured hemisphere. In conclusion, 002C-3 shows a neuroprotective effect on tMCAO injury in mice, and its mechanisms may be associated with alleviation of blood-brain barrier damage caused by the activation of MMPs, inhibition of autophagy, and stimulation of calcium signals related to cell survival. These findings suggest that 002C-3 is a neuroprotective agent that acts on multiple pathways.

Key words: 002C-3, Cerebral ischemia-reperfusion, Microvascular permeability, Autophagy, CaMKK/CaMKIV/HDAC4 pathway

CLC Number: 

Supporting: