Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation
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.
KeywordsCerebral ischemia-reperfusion injury Mitophagy Naringin Nitrative stress Peroxynitrite
This work was supported by the National Natural Science Foundation of China (No. 31570855), the Research Grants Council, Hong Kong SAR (No. 17118717, No. 17102915), and Areas of Excellence Scheme 2016/17 AoE/P-705/16.
J.-H.F. designed and performed experiments, analyzed the data, and wrote the manuscript. J.-G.S. received funding, conceived and supervised the research designs and experiments, and co-wrote the manuscript. X.-M.C. detected ONOO− with probes and analyzed data. S.-W.L. conducted pharmacokinetics study of naringin with UPLC-MS/MS. W.-T.L. detected ONOO− scavenging capability of naringin with UPLC. D.Y. contributed to HKYellow-AM probe design and development. W.-W.S. supervised naringin compound extraction and designed animal experiments about naringin. X.-J.W. received funding, supervised and designed pharmacokinetics study, and designed the experiments.
Compliance with Ethical Standards
The authors declare that they have no competing interests.
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