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Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation

  • Jinghan Feng
  • Xingmiao Chen
  • Shengwen Lu
  • Wenting Li
  • Dan Yang
  • Weiwei Su
  • Xijun Wang
  • Jiangang Shen
Article

Abstract

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.

Keywords

Cerebral ischemia-reperfusion injury Mitophagy Naringin Nitrative stress Peroxynitrite 

Notes

Acknowledgements

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.

Author Contributions

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

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2018_1027_MOESM1_ESM.docx (302 kb)
ESM 1 (DOCX 301 kb)

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Authors and Affiliations

  1. 1.School of Chinese Medicine, LKS Faculty of MedicineThe University of Hong KongHong KongChina
  2. 2.National TCM Key Laboratory of Serum Pharmacochemistry, Key Lab of Chinmedomics, Department of Pharmaceutical AnalysisHeilongjiang University of Chinese MedicineHarbinChina
  3. 3.Morningside Laboratory for Chemical Biology and Department of ChemistryThe University of Hong KongHong KongChina
  4. 4.Guangzhou Quality R&D Center of Traditional Chinese Medicine, Guangdong Key Laboratory of Plant Resources, School of Life SciencesSun Yat-sen UniversityGuangzhouChina

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