Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015, 386: 896–902.

    Article  CAS  PubMed  Google Scholar 

  2. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009, 373: 2055–2066.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  20. Franklin Keith BJ, Paxinos G. The Mouse Brain in Stereotaxic Coordinates. 3rd ed. San Diego: Academic Press, 2007: 52–63.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  22. Wang WA, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta 2014, 1843: 2143–2149.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  24. Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses. Gene Expr 1999, 7: 321–335.

    CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  28. Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ. Redox Homeostasis and Mitochondrial Dynamics. Cell Metab 2015, 22: 207–218.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  33. Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinson’s disease. Free Radic Biol Med 2013, 62: 13–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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!).

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China

    Qing Zhao, Yuqing Hou, Lijun Zhang, Jiwei Cheng, Yuan Shen & Yu Bai

  2. Department of Emergency Internal Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China

    Xiaoyan Yang

  3. Laboratory of Neurology, Institute of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Dingfang Cai

  4. Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Dingfang Cai

  5. Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People’s Hospital Affiliated with Tongji University School of Medicine, Shanghai, 200072, China

    Ling Ye & Kaizhe Wang

  6. Department of Immunology, Tongji University School of Medicine, Shanghai, 200092, China

    Ling Ye

Authors
  1. Qing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dingfang Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ling Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuqing Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lijun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiwei Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kaizhe Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yu Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Qing Zhao or Yu Bai.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 208 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Q., Yang, X., Cai, D. et al. Echinacoside Protects Against MPP+-Induced Neuronal Apoptosis via ROS/ATF3/CHOP Pathway Regulation. Neurosci. Bull. 32, 349–362 (2016). https://doi.org/10.1007/s12264-016-0047-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-016-0047-4

Keywords

Search

Navigation