Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α.
Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α.
复制标题
右美托咪定通过上调 HIF-1α 抑制神经元自噬保护小鼠脑免受缺血再灌注损伤
DOI：
10.3389/fncel.2017.00197
复制
发表时间：
2017
影响因子：
5.3
通讯作者：
Tao T
中科院分区：
文献类型：
--
作者：
Luo C;Ouyang MW;Fang YY;Li SJ;Zhou Q;Fan J;Qin ZS;Tao T
在过去的几十年里，中风是中国的首要死因，并产生了沉重的社会经济负担。以往的研究表明，右旋美托咪定(DEX)对脑缺血后具有神经保护作用。然而，自噬在DEX介导的脑缺血后神经保护中的作用仍不清楚。在本研究中，我们发现与DEX+RAPA(自噬诱导剂)相比，DEX和DEX+3-甲基腺嘌呤(3-MA)(自噬抑制剂)的后处理可以缩小小鼠大脑中动脉闭塞(TMCAO)模型24小时的脑梗塞面积，并改善神经功能障碍。地塞米松可抑制缺血区神经元的自噬，增加原代培养神经元的存活率，减少细胞凋亡率。地塞米松通过抑制细胞凋亡和自噬，诱导原代培养神经元表达Bcl1和p62，降低微管相关蛋白1轻链3和Beclin 1的表达。同时，地塞米松在体内外均能促进缺氧诱导因子-1α(HIF-1α)的表达，其抑制剂2-甲氧基雌二醇(2ME2)可逆转地塞米松诱导的自噬抑制作用。综上所述，我们的研究表明，再灌流开始时给予地塞米松的后处理可通过上调HIF-1α来抑制神经元自噬，从而保护小鼠的脑缺血再灌注损伤，这为急性缺血性损伤提供了一种潜在的治疗方法。
Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3-MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared with DEX+RAPA (autophagy inducer) 24 h after transient middle cerebral artery artery occlusion (tMCAO) model in mice. DEX inhibited the neuronal autophagy in the peri-ischemic brain, and increased viability and decreased apoptosis of primary cultured neurons in oxygen-glucose deprivation (OGD) model. DEX induced expression of Bcl-1 and p62, while reduced the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in primary cultured neurons through inhibition of apoptosis and autophagy. Meanwhile, DEX promoted the expression of hypoxia-inducible factor-1α (HIF-1α) both in vivo and in vitro, and 2-Methoxyestradiol (2ME2), an inhibitor of HIF-1α, could reverse DEX-induced autophagic inhibition. In conclusion, our study suggests that post-conditioning with DEX at the beginning of reperfusion protects mouse brain from ischemia-reperfusion injury via inhibition of neuronal autophagy by upregulation of HIF-1α, which provides a potential therapeutic treatment for acute ischemic injury.