Abstract
Oxidative stress plays a crucial role in the occurrence and development of Parkinson’s disease (PD). Rutin, a natural botanical ingredient, has been shown to have antioxidant properties. Therefore, the aim of this study was to investigate the neuroprotective effects of rutin on PD and the underlying mechanisms. MPP+(1-methyl-4-phenylpyridinium ions)-treated SH-SY5Y cells were used as an in vitro model of PD. Human PHB2-shRNA lentiviral particles were transfected into SH-SY5Y cells to interfere with the expression of Prohibitin2 (PHB2). The oxidative damage of cells was analyzed by detecting intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and mitochondrial membrane potential (MMP). Western blotting was used to detect the protein expression of antioxidant factors such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO-1), and mitophagy factors PHB2, translocase of outer mitochondrial membrane 20 (TOM20), and LC3II/LC3I (microtubule-associated protein II light chain 3 (LC3II) to microtubule-associated protein I light chain 3 (LC3I)). In addition, we also examined the expression of PHB2 and LC3II/LC3I by immunofluorescence staining. MPP+ treatment significantly increased the generation of ROS and MDA and the level of MMP depolarization and decreased the protein expression of Nrf2, HO-1, NQO1, TOM20, PHB2, and LC3II/LC3I. In MPP+-treated SH-SY5Y cells, rutin significantly decreased the generation of ROS and MDA and the level of MMP depolarization and increased the protein expression of Nrf2, HO-1, NQO-1, TOM20, PHB2, and LC3II/LC3I. However, the protective role of rutin was inhibited in PHB2-silenced cells. Rutin attenuates oxidative damage which may be associated with PHB2-mediated mitophagy in MPP+-induced SH-SY5Y cells. Rutin might be used as a potential drug for the prevention and treatment of PD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of Data and Materials
All the data generated or analyzed during this study are included in this published article; further inquiries can be directed to the corresponding authors.
Abbreviations
- MPP+ :
-
1-Methyl-4-phenylpyridinium ions
- DA neurons:
-
Dopaminergic neurons
- ROS:
-
Reactive oxygen species
- MDA:
-
Malondialdehyde
- MMP:
-
Mitochondrial membrane potential
- Nrf2:
-
Nuclear factor E2-related factor 2
- HO-1:
-
Heme oxygenase-1
- NQO-1:
-
NADPH quinone oxidoreductase-1
- TOM20:
-
Translocase of outer mitochondrial membrane 20
- PHB2:
-
Prohibitin 2
- LC3II/LC3I:
-
Microtubule-associated protein II light chain 3 (LC3 II) to microtubule-associated protein I light chain 3 (LC3 I)
References
Archibald NK, Clarke MP, Mosimann UP, Burn DJ (2009) The retina in Parkinson’s disease. Brain 132:1128–1145. https://doi.org/10.1093/brain/awp068
Budzynska B, Faggio C, Kruk-Slomka M, Samec D, Nabavi SF, Sureda A, Devi KP, Nabavi SM (2019) Rutin as neuroprotective agent: from bench to bedside. Curr Med Chem 26:5152–5164. https://doi.org/10.2174/0929867324666171003114154
Christmann A, Gries M, Scholz P, Stahr PL, Law JKY, Schulte S, Martin M, Lilischkis R, Ingebrandt S, Keck CM et al (2022) The antioxidant rutin counteracts the pathological impact of α-synuclein on the enteric nervous system in vitro. Biol Chem 403:103–122. https://doi.org/10.1515/hsz-2021-0259
Clark EH, Vazquez de la Torre A, Hoshikawa T, Briston T (2021) Targeting mitophagy in Parkinson's disease. J Biol Chem 296:100209. https://doi.org/10.1074/jbc.REV120.014294
De Rasmo D, Ferretta A, Russo S, Ruggieri M, Lasorella P, Paolicelli D, Trojano M, Signorile A (2020) PBMC of multiple sclerosis patients show deregulation of OPA1 processing associated with increased ROS and PHB2 protein levels. Biomedicines 8. https://doi.org/10.3390/biomedicines8040085
Di Rita A, Strappazzon F (2019) Mitophagy could fight Parkinson’s disease through antioxidant action. Rev Neurosci 30:729–742. https://doi.org/10.1515/revneuro-2018-0095
Enogieru AB, Haylett W, Hiss DC, Bardien S, Ekpo OE (2018) Rutin as a potent antioxidant: implications for neurodegenerative disorders. Oxid Med Cell Longev 2018:6241017. https://doi.org/10.1155/2018/6241017
Ganeshpurkar A, Saluja AK (2017) The Pharmacological potential of rutin. Saudi Pharm J 25:149–164. https://doi.org/10.1016/j.jsps.2016.04.025
Guyot AC, Leuxe C, Disdier C, Oumata N, Costa N, Roux GL, Varela PF, Duchon A, Charbonnier JB, Herault Y et al (2020) A small compound targeting prohibitin with potential interest for cognitive deficit rescue in aging mice and tau pathology treatment. Sci Rep 10:1143. https://doi.org/10.1038/s41598-020-57560-3
He J, Zhu G, Wang G, Zhang F (2020) Oxidative stress and neuroinflammation potentiate each other to promote progression of dopamine neurodegeneration. Oxid Med Cell Longev 2020:6137521. https://doi.org/10.1155/2020/6137521
Iridoy MO, Zubiri I, Zelaya MV, Martinez L, Ausin K, Lachen-Montes M, Santamaria E, Fernandez-Irigoyen J, Jerico I (2018) Neuroanatomical quantitative proteomics reveals common pathogenic biological routes between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intern J Mole sci 20. https://doi.org/10.3390/ijms20010004
Jung KA, Kwak MK (2010) The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules (basel, Switzerland) 15:7266–7291. https://doi.org/10.3390/molecules15107266
Ke B, Zhang T, An T, Lu R (2020) Soy isoflavones ameliorate the cognitive dysfunction of Goto-Kakizaki rats by activating the Nrf2-HO-1 signalling pathway. Aging 12:21344–21354. https://doi.org/10.18632/aging.103877
Khan MM, Raza SS, Javed H, Ahmad A, Khan A, Islam F, Safhi MM, Islam F (2012) Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson’s disease. Neurotox Res 22:1–15. https://doi.org/10.1007/s12640-011-9295-2
Magalingam KB, Radhakrishnan A, Haleagrahara N (2013) Rutin, a bioflavonoid antioxidant protects rat pheochromocytoma (PC-12) cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Int J Mol Med 32:235–240. https://doi.org/10.3892/ijmm.2013.1375
Magalingam KB, Radhakrishnan A, Haleagrahara N (2016) Protective effects of quercetin glycosides, rutin, and isoquercetrin against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in rat pheochromocytoma (PC-12) cells. Int J Immunopathol Pharmacol 29:30–39. https://doi.org/10.1177/0394632015613039
Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ (2021) Mitochondrial dysfunction and mitophagy in Parkinson’s disease: from mechanism to therapy. Trends Biochem Sci 46:329–343. https://doi.org/10.1016/j.tibs.2020.11.007
Pan RY, Ma J, Kong XX, Wang XF, Li SS, Qi XL, Yan YH, Cheng J, Liu Q, Jin W et al (2019) Sodium rutin ameliorates Alzheimer's disease-like pathology by enhancing microglial amyloid-β clearance. Science advances 5:eaau6328. https://doi.org/10.1126/sciadv.aau6328
Pant C, Chakrabarti M, Mendonza JJ, Ganganna B, Pabbaraja S, Pal Bhadra M (2021) Aza-flavanone diminishes parkinsonism in the drosophila melanogaster parkin mutant. ACS Chem Neurosci 12:4380–4392. https://doi.org/10.1021/acschemneuro.1c00285
Park SE, Sapkota K, Choi JH, Kim MK, Kim YH, Kim KM, Kim KJ, Oh HN, Kim SJ, Kim S (2014) Rutin from Dendropanax morbifera Leveille protects human dopaminergic cells against rotenone induced cell injury through inhibiting JNK and p38 MAPK signaling. Neurochem Res 39:707–718. https://doi.org/10.1007/s11064-014-1259-5
Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ (2019) Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med 51:1–13. https://doi.org/10.1038/s12276-019-0355-7
Risiglione P, Leggio L, Cubisino SAM, Reina S, Paternò G, Marchetti B, Magrì A, Iraci N, Messina A (2020) High-resolution respirometry reveals MPP(+) mitochondrial toxicity mechanism in a cellular model of parkinson's disease. Intern J Mole Sci 21. https://doi.org/10.3390/ijms21217809
Schapira AH, Olanow CW, Greenamyre JT, Bezard E (2014) Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet (london, England) 384:545–555. https://doi.org/10.1016/s0140-6736(14)61010-2
Sharma S, Narang JK, Ali J, Baboota S (2016) Synergistic antioxidant action of vitamin E and rutin SNEDDS in ameliorating oxidative stress in a Parkinson's disease model. Nanotechnol 27:375101. https://doi.org/10.1088/0957-4484/27/37/375101
Shefa U, Jeong NY, Song IO, Chung HJ, Kim D, Jung J, Huh Y (2019) Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res 14:749–756. https://doi.org/10.4103/1673-5374.249218
Subramaniam SR, Chesselet MF (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106–107:17–32. https://doi.org/10.1016/j.pneurobio.2013.04.004
Sun Y, Sukumaran P, Selvaraj S, Cilz NI, Schaar A, Lei S, Singh BB (2018) TRPM2 promotes neurotoxin MPP(+)/MPTP-induced cell death. Mol Neurobiol 55:409–420. https://doi.org/10.1007/s12035-016-0338-9
Trist BG, Hare DJ, Double KL (2019) Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging cell 18:e13031. https://doi.org/10.1111/acel.13031
Wang J, Zhu P, Li R, Ren J, Zhang Y, Zhou H (2020) Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2. Theranostics 10:384–397. https://doi.org/10.7150/thno.40098
Waz S, Heeba GH, Hassanin SO, Abdel-Latif RG (2021) Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway. Life sciences 264:118630. https://doi.org/10.1016/j.lfs.2020.118630
Wei Y, Chiang WC, Sumpter Jr R, Mishra P, Levine B (2017) Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168:224–238 e210. https://doi.org/10.1016/j.cell.2016.11.042
Xu Y, Wang J, Xu W, Ding F, Ding W (2019) Prohibitin 2-mediated mitophagy attenuates renal tubular epithelial cells injury by regulating mitochondrial dysfunction and NLRP3 inflammasome activation. Am J Physiol Renal Physiol 316:F396–F407. https://doi.org/10.1152/ajprenal.00420.2018
Yan C, Gong L, Chen L, Xu M, Abou-Hamdan H, Tang M, Desaubry L, Song Z (2020) PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 16:419–434. https://doi.org/10.1080/15548627.2019.1628520
Zhang T, Wu P, Budbazar E, Zhu Q, Sun C, Mo J, Peng J, Gospodarev V, Tang J, Shi H et al (2019) Mitophagy reduces oxidative stress via keap1 (Kelch-like epichlorohydrin-associated protein 1)/Nrf2 (nuclear factor-E2-related factor 2)/PHB2 (prohibitin 2) pathway after subarachnoid hemorrhage in rats. Stroke 50:978–988. https://doi.org/10.1161/STROKEAHA.118.021590
Zhao Y, Sun Y, Wang G, Ge S, Liu H (2019) Dendrobium officinale polysaccharides protect against MNNG-induced PLGC in rats via activating the NRF2 and antioxidant enzymes HO-1 and NQO-1. Oxid Med Cell Longev 2019:9310245. https://doi.org/10.1155/2019/9310245
Acknowledgements
We wish to thank you for the research instrument support provided by the Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, the First Affiliated Hospital, and the College of Clinical Medicine of Henan University of Science and Technology.
Funding
This work was supported by the Henan Medical Science and Technology Research Program Joint Construction Project LHGJ20200566, LHGJ20200567, and LHGJ20210593; the Key Science and Technology Research of Henan Province 222102310351 and 212102310216; and the Henan Medical Science and Technology Research Program province-ministry co-sponsorship SBGJ202002099.
Author information
Authors and Affiliations
Contributions
J.Q.Y. and X.Y.L. conceived the study and designed experiments. Y.J.Z and J.N.W. performed experiments and analyzed the results. M.M.S and S.Y.Y. performed the analysis of Western Blotting and microscopy images. J.Q.Y. and X.Y.L. wrote the main manuscript. All authors reviewed and edited the manuscript.
Corresponding author
Ethics declarations
Ethical Approval
The SH-SY5Y cell line used in this study was provided by the Hepatology Laboratory of the Third Affiliated Hospital of Sun Yat-sen University in 2017. This study was approved by the Ethics Committee of the First Affiliated Hospital of Henan University of Science and Technology (approval number: 2020–0072).
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lai, X., Zhang, Y., Wu, J. et al. Rutin Attenuates Oxidative Stress Via PHB2-Mediated Mitophagy in MPP+-Induced SH-SY5Y Cells. Neurotox Res 41, 242–255 (2023). https://doi.org/10.1007/s12640-023-00636-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-023-00636-5