Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation
Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation
复制标题
柚皮苷通过抑制过氧亚硝酸盐介导的线粒体自噬激活减轻脑缺血再灌注损伤
DOI：
10.1007/s12035-018-1027-7
复制
发表时间：
2018-12-01
影响因子：
5.1
通讯作者：
Shen, Jiangang
中科院分区：
文献类型：
--
作者：
Feng, Jinghan;Chen, Xingmiao;Shen, Jiangang
过度的自噬/线粒体自噬在脑缺血再灌注损伤中起重要作用。过氧亚硝酸盐（ONOO-）是一种典型的活性氮，介导过度的线粒体自噬激活，加重脑I/R损伤。在本研究中，我们验证了这样一个假设，即天然抗氧化剂柚皮苷可以抑制ONOO-介导的线粒体自噬激活，减轻脑I/R损伤。首先，我们证明了柚皮苷具有很强的ONOO-清除能力，并抑制了SH-SY 5 Y细胞在缺氧缺糖10 h+复氧14 h或ONOO-供体3-morpholinosynonimine条件下超氧阴离子和一氧化氮的产生。柚苷还能抑制缺血2 h再灌注22 h大鼠脑组织NADPH氧化酶亚基和iNOS的表达。接下来，我们发现柚苷能够穿过血脑屏障，并且柚苷降低了缺血再灌注大鼠脑中的神经功能缺损评分，减小了梗死面积，并减弱了凋亡细胞死亡。此外，柚苷减少3-硝基酪氨酸的形成，降低LC 3-II与LC 3-I的线粒体组分的比例，并抑制帕金易位到线粒体。综上所述，柚苷可能是一种潜在的治疗剂，通过减轻ONOO-介导的过度线粒体自噬来预防脑I/R损伤。
Excessive autophagy/mitophagy plays important roles during cerebral ischemia-reperfusion (I/R) injury. Peroxynitrite (ONOO-), a representative reactive nitrogen species, mediates excessive mitophagy activation and exacerbates cerebral I/R injury. In the present study, we tested the hypothesis that naringin, a natural antioxidant, could inhibit ONOO--mediated mitophagy activation and attenuate cerebral I/R injury. Firstly, we demonstrated that naringin possessed strong ONOO- scavenging capability and also inhibited the production of superoxide and nitric oxide in SH-SY5Y cells exposed to 10h oxygen-glucose-deprivation plus 14h of reoxygenation or ONOO- donor 3-morpholinosydnonimine conditions. Naringin also inhibited the expression of NADPH oxidase subunits and iNOS in rat brains subjected to 2h ischemia plus 22h reperfusion. Next, we found that naringin was able to cross the blood-brain barrier, and naringin decreased neurological deficit score, reduced infarct size, and attenuated apoptotic cell death in the ischemia-reperfused rat brains. Furthermore, naringin reduced 3-nitrotyrosine formation, decreased the ratio of LC3-II to LC3-I in mitochondrial fraction, and inhibited the translocation of Parkin to the mitochondria. Taken together, naringin could be a potential therapeutic agent to prevent the brain from I/R injury via attenuating ONOO--mediated excessive mitophagy.