School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Room 110, 1/F, No.10, Sassoon Road, Pokfulam, Hong Kong, SAR, China.
National TCM Key Laboratory of Serum Pharmacochemistry, Key Lab of Chinmedomics, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin, China.
Mol Neurobiol. 2018 Dec;55(12):9029-9042. doi: 10.1007/s12035-018-1027-7. Epub 2018 Apr 7.
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 10 h oxygen-glucose-deprivation plus 14 h of reoxygenation or ONOO donor 3-morpholinosydnonimine conditions. Naringin also inhibited the expression of NADPH oxidase subunits and iNOS in rat brains subjected to 2 h ischemia plus 22 h 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.
过量的自噬/线粒体自噬在脑缺血再灌注（I/R）损伤中起着重要作用。过氧亚硝酸盐（ONOO），一种代表性的活性氮物种，介导过量的线粒体自噬激活，并加重脑 I/R 损伤。在本研究中，我们检验了柚皮苷（一种天然抗氧化剂）是否能抑制 ONOO 介导的线粒体自噬激活并减轻脑 I/R 损伤的假说。首先，我们证明柚皮苷具有很强的 ONOO 清除能力，还能抑制暴露于 10 h 氧葡萄糖剥夺加 14 h 复氧或 ONOO 供体 3-吗啉代-sydnonimine 条件下的 SH-SY5Y 细胞中超氧自由基和一氧化氮的产生。柚皮苷还抑制了大鼠脑缺血再灌注 2 h 加再灌注 22 h 后 NADPH 氧化酶亚基和 iNOS 的表达。接下来，我们发现柚皮苷能够穿过血脑屏障，柚皮苷降低了缺血再灌注大鼠的神经功能缺损评分，减少了梗死面积，并减轻了凋亡细胞死亡。此外，柚皮苷减少了 3-硝基酪氨酸的形成，降低了线粒体部分 LC3-II 与 LC3-I 的比值，并抑制了 Parkin 向线粒体的易位。综上所述，柚皮苷可能是一种通过减轻 ONOO 介导的过量线粒体自噬来预防脑 I/R 损伤的潜在治疗药物。
