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

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:0...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.National Natural Science Foundation of China,Beijing Natural Science Foundation中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)08598-6042