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

002C-3通过抑制MMPs和细胞自噬并激活细胞存活相关的钙信号通路保护小鼠脑缺血再灌注损伤（英文）

作　　者：Jingliang Zhang Tao Hu Xiaoyan Liu Yuanjun Zhu Xiaoling Chen Ye Liu Yinye Wang 张精亮;胡涛;刘晓岩;朱元军;陈晓玲;刘晔;王银叶(北京大学医学部药学院分子与细胞药理学系,北京100191;北京红惠新药科技有限公司,北京102600)

机构地区：[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

出　　处：《Journal of Chinese Pharmaceutical Sciences》2016年第8期598-604,共7页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No.81302763,81573333);Beijing Natural Science Foundation(Grant No.7144218)

摘　　要：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 pg/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 150μg/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 pg/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.研究厚朴酚衍生物002C-3对小鼠中脑动脉缺血(MCAO)再灌注损伤的作用及可能的机制。与模型对照组相比,在缺血1.5 h后单次静注002C-3(100和150μg/kg)可明显减小神经缺陷评分,缩小脑梗死体积和降低脑水含量。002C-3(75–150μg/kg)可明显减少脑毛细血管伊文氏蓝的渗出量。与模型对照组相比,002C-3(100μg/kg)可明显抑制缺血半脑组织中的基质金属蛋白酶MMP-9和MMP-2的活性;减少自噬相关蛋白Beclin-1和LC3B-Ⅱ的表达,增加p-62蛋白的表达;002C-3还可增加细胞存活相关的钙信号蛋白p-CaMKIV和p-HDAC4的表达。这些结果表明:002C-3在小鼠脑缺血再灌注损伤模型上有明显的神经保护作用,其作用机制可能与抑制MMPs活性,保护血脑屏障,抑制缺血诱导的细胞自噬以及激活细胞存活相关的钙信号通路有关。

关 键 词：002C-3 Cerebral ischemia-reperfusion Microvascular permeability AUTOPHAGY CaMKK/CaMKIV/HDAC4 pathway 

分 类 号：R285.5[医药卫生—中药学]