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Neuroscience Bulletin

, Volume 32, Issue 4, pp 349–362 | Cite as

Echinacoside Protects Against MPP+-Induced Neuronal Apoptosis via ROS/ATF3/CHOP Pathway Regulation

  • Qing Zhao
  • Xiaoyan Yang
  • Dingfang Cai
  • Ling Ye
  • Yuqing Hou
  • Lijun Zhang
  • Jiwei Cheng
  • Yuan Shen
  • Kaizhe Wang
  • Yu Bai
Original Article

Abstract

Echinacoside (ECH) is protective in a mouse model of Parkinson’s disease (PD) induced by 1-methyl-4-phenylpyridinium ion (MPP+). To investigate the mechanisms involved, SH-SY5Y neuroblastoma cells were treated with MPP+ or a combination of MPP+ and ECH, and the expression of ATF3 (activating transcription factor 3), CHOP (C/EBP-homologous protein), SCNA (synuclein alpha), and GDNF (glial cell line-derived neurotrophic factor) was assessed. The results showed that ECH significantly improved cell survival by inhibiting the generation of MPP+-induced reactive oxygen species (ROS). In addition, ECH suppressed the ROS and MPP+-induced expression of apoptotic genes (ATF3, CHOP, and SCNA). ECH markedly decreased the MPP+-induced caspase-3 activity in a dose-dependent manner. ATF3-knockdown also decreased the CHOP and cleaved caspase-3 levels and inhibited the apoptosis induced by MPP+. Interestingly, ECH partially restored the GDNF expression that was down-regulated by MPP+. ECH also improved dopaminergic neuron survival during MPP+ treatment and protected these neurons against the apoptosis induced by MPTP. Taken together, these data suggest that the ROS/ATF3/CHOP pathway plays a critical role in mechanisms by which ECH protects against MPP+-induced apoptosis in PD.

Keywords

Echinacoside Parkinson’s disease 1-Methyl-4-phenylpyridinium ion Reactive oxygen species ATF3 CHOP 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81202814), the Shanghai Municipal Commission of Health and Family Planning (20124y116) and the Young Teachers Training Funding Scheme of Shanghai Colleges and Universities, China (zzszy12026). We thank Dr. Yunsheng Yuan, Professor Dazheng Wu, and Associate Professor Peihao Yin for their guidance on the experiments and preparation of the manuscript.

Supplementary material

12264_2016_47_MOESM1_ESM.pdf (209 kb)
Supplementary material 1 (PDF 208 kb)

References

  1. 1.
    Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015, 386: 896–902.CrossRefPubMedGoogle Scholar
  2. 2.
    Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009, 373: 2055–2066.CrossRefPubMedGoogle Scholar
  3. 3.
    Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol 2015, 14: 518–531.CrossRefPubMedGoogle Scholar
  4. 4.
    Lehri-Boufala S, Ouidja MO, Barbier-Chassefiere V, Henault E, Raisman-Vozari R, Garrigue-Antar L, et al. New roles of glycosaminoglycans in alpha-synuclein aggregation in a cellular model of Parkinson disease. PLoS One 2015, 10: e0116641.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Duka T, Duka V, Joyce JN, Sidhu A. Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson’s disease models. FASEB J 2009, 23: 2820–2830.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang ZG, Wu L, Wang JL, Yang JD, Zhang J, Li LH, et al. Astragaloside IV prevents MPP(+)-induced SH-SY5Y cell death via the inhibition of Bax-mediated pathways and ROS production. Mol Cell Biochem 2012, 364: 209–216.CrossRefPubMedGoogle Scholar
  7. 7.
    Lee DH, Kim CS, Lee YJ. Astaxanthin protects against MPTP/MPP+-induced mitochondrial dysfunction and ROS production in vivo and in vitro. Food Chem Toxicol 2010, 49: 271–280.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ye Q, Huang B, Zhang X, Zhu Y, Chen X. Astaxanthin protects against MPP(+)-induced oxidative stress in PC12 cells via the HO-1/NOX2 axis. BMC Neurosci 2013, 13: 156.CrossRefGoogle Scholar
  9. 9.
    Conn KJ, Gao WW, Ullman MD, McKeon-O’Malley C, Eisenhauer PB, Fine RE, et al. Specific up-regulation of GADD153/CHOP in 1-methyl-4-phenyl-pyridinium-treated SH-SY5Y cells. J Neurosci Res 2002, 68: 755–760.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhao Q, Gao J, Li W, Cai D. Neurotrophic and neurorescue effects of Echinacoside in the subacute MPTP mouse model of Parkinson’s disease. Brain Res 2010, 1346: 224–236.CrossRefPubMedGoogle Scholar
  11. 11.
    Geng X, Tian X, Tu P, Pu X. Neuroprotective effects of echinacoside in the mouse MPTP model of Parkinson’s disease. Eur J Pharmacol 2007, 564: 66–74.CrossRefPubMedGoogle Scholar
  12. 12.
    Deng M, Zhao JY, Tu PF, Jiang Y, Li ZB, Wang YH. Echinacoside rescues the SHSY5Y neuronal cells from TNFalpha-induced apoptosis. Eur J Pharmacol 2004, 505: 11–18.CrossRefPubMedGoogle Scholar
  13. 13.
    Wang YH, Xuan ZH, Tian S, Du GH. Echinacoside Protects against 6-Hydroxydopamine-Induced Mitochondrial Dysfunction and Inflammatory Responses in PC12 Cells via Reducing ROS Production. Evid Based Complement Alternat Med 2015, 2015: 189–239.Google Scholar
  14. 14.
    Zhao Q, Cai D, Bai Y. Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease. Int J Mol Med 2013, 32: 883–891.PubMedGoogle Scholar
  15. 15.
    Lingor P, Unsicker K, Krieglstein K. Midbrain dopaminergic neurons are protected from radical induced damage by GDF-5 application. Short communication. J Neural Transm (Vienna) 1999, 106: 139–144.CrossRefGoogle Scholar
  16. 16.
    Hegarty SV, Collins LM, Gavin AM, Roche SL, Wyatt SL, Sullivan AM, et al. Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons. Neuromolecular Med 2014, 16: 473–489.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang H, Mo P, Ren S, Yan C. Activating transcription factor 3 activates p53 by preventing E6-associated protein from binding to E6. J Biol Chem 2010, 285: 13201–13210.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Weng S, Zhou L, Deng Q, Wang J, Yu Y, Zhu J, et al. Niclosamide induced cell apoptosis via upregulation of ATF3 and activation of PERK in Hepatocellular carcinoma cells. BMC Gastroenterol 2016, 16: 25.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yuan Y, Zhang X, Weng S, Guan W, Xiang D, Gao J, et al. Expression and purification of bioactive high-purity recombinant mouse SPP1 in Escherichia coli. Appl Biochem Biotechnol 2014, 173: 421–432.CrossRefPubMedGoogle Scholar
  20. 20.
    Franklin Keith BJ, Paxinos G. The Mouse Brain in Stereotaxic Coordinates. 3rd ed. San Diego: Academic Press, 2007: 52–63.Google Scholar
  21. 21.
    Zhu M, Zhou M, Shi Y, Li WW. Effects of echinacoside on MPP(+)-induced mitochondrial fragmentation, mitophagy and cell apoptosis in SH-SY5Y cells. Journal of Chinese Integrative Medicine 2012, 10: 1427–1432.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang WA, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta 2014, 1843: 2143–2149.CrossRefPubMedGoogle Scholar
  23. 23.
    Tian Z, An N, Zhou B, Xiao P, Kohane IS, Wu E. Cytotoxic diarylheptanoid induces cell cycle arrest and apoptosis via increasing ATF3 and stabilizing p53 in SH-SY5Y cells. Cancer Chemother Pharmacol 2009, 63: 1131–1139.CrossRefPubMedGoogle Scholar
  24. 24.
    Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses. Gene Expr 1999, 7: 321–335.PubMedGoogle Scholar
  25. 25.
    Li Y, Guo Y, Tang J, Jiang J, Chen Z. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim Biophys Sin (Shanghai) 2015, 47: 146–147.CrossRefGoogle Scholar
  26. 26.
    Heilmann J, Calis I, Kirmizibekmez H, Schuhly W, Harput S, Sticher O. Radical scavenger activity of phenylethanoid glycosides in FMLP stimulated human polymorphonuclear leukocytes: structure-activity relationships. Planta Med 2000, 66: 746–748.CrossRefPubMedGoogle Scholar
  27. 27.
    Indo HP, Yen HC, Nakanishi I, Matsumoto K, Tamura M, Nagano Y, et al. A mitochondrial superoxide theory for oxidative stress diseases and aging. J Clin Biochem Nutr 2015, 56: 1–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ. Redox Homeostasis and Mitochondrial Dynamics. Cell Metab 2015, 22: 207–218.CrossRefPubMedGoogle Scholar
  29. 29.
    Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal MF. Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Antioxid Redox Signal 2009, 11: 2095–2104.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cartelli D, Ronchi C, Maggioni MG, Rodighiero S, Giavini E, Cappelletti G. Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP + -induced neurodegeneration. J Neurochem 2010, 115: 247–258.CrossRefPubMedGoogle Scholar
  31. 31.
    Jantas D, Greda A, Golda S, Korostynski M, Grygier B, Roman A, et al. Neuroprotective effects of metabotropic glutamate receptor group II and III activators against MPP(+)-induced cell death in human neuroblastoma SH-SY5Y cells: the impact of cell differentiation state. Neuropharmacology 2014, 83: 36–53.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu Z, Chen HQ, Huang Y, Qiu YH, Peng YP. Transforming growth factor-beta1 acts via TbetaR-I on microglia to protect against MPP(+)-induced dopaminergic neuronal loss. Brain Behav Immun 2016, 51: 131–143.CrossRefPubMedGoogle Scholar
  33. 33.
    Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinson’s disease. Free Radic Biol Med 2013, 62: 13–25.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wei R, Zhang R, Xie Y, Shen L, Chen F. Hydrogen Suppresses Hypoxia/Reoxygenation-Induced Cell Death in Hippocampal Neurons Through Reducing Oxidative Stress. Cell Physiol Biochem 2015, 36: 585–598.CrossRefPubMedGoogle Scholar
  35. 35.
    Jiang H, Ren Y, Zhao J, Feng J. Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet 2004, 13: 1745–1754.CrossRefPubMedGoogle Scholar
  36. 36.
    Khwanraj K, Phruksaniyom C, Madlah S, Dharmasaroja P. Differential Expression of Tyrosine Hydroxylase Protein and Apoptosis-Related Genes in Differentiated and Undifferentiated SH-SY5Y Neuroblastoma Cells Treated with MPP+. Neurol Res Int 2015, 2015: 734703. (Add doi or add pages!).Google Scholar
  37. 37.
    Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 2004, 24: 1365–1377.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Xu L, Su L, Liu X. PKCdelta regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells. Mol Cancer Ther 2012, 11: 2174–2182.CrossRefPubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore 2016

Authors and Affiliations

  • Qing Zhao
    • 1
  • Xiaoyan Yang
    • 2
  • Dingfang Cai
    • 3
    • 4
  • Ling Ye
    • 5
    • 6
  • Yuqing Hou
    • 1
  • Lijun Zhang
    • 1
  • Jiwei Cheng
    • 1
  • Yuan Shen
    • 1
  • Kaizhe Wang
    • 5
  • Yu Bai
    • 1
  1. 1.Department of Neurology, Putuo HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
  2. 2.Department of Emergency Internal Medicine, Putuo HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
  3. 3.Laboratory of Neurology, Institute of Integrative Medicine, Zhongshan HospitalFudan UniversityShanghaiChina
  4. 4.Department of Integrative Medicine, Zhongshan HospitalFudan UniversityShanghaiChina
  5. 5.Center for Translational Neurodegeneration and Regenerative TherapyShanghai Tenth People’s Hospital Affiliated with Tongji University School of MedicineShanghaiChina
  6. 6.Department of ImmunologyTongji University School of MedicineShanghaiChina

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