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Rutin from Dendropanax morbifera Leveille Protects Human Dopaminergic Cells Against Rotenone Induced Cell Injury Through Inhibiting JNK and p38 MAPK Signaling

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Abstract

Dendropanax morbifera Leveille (Araliaceae) is well known in Korean traditional medicine for a variety of diseases. Rotenone is a commonly used neurotoxin to produce in vivo and in vitro Parkinson’s disease models. This study was designed to elucidate the processes underlying neuroprotection of rutin, a bioflavonoid isolated from D. morbifera Leveille in cellular models of rotenone-induced toxicity. We found that rutin significantly decreased rotenone-induced generation of reactive oxygen species levels in SH-SY5Y cells. Rutin protected the increased level of intracellular Ca2+ and depleted level of mitochondrial membrane potential (ΔΨm) induced by rotenone. Furthermore, it prevented the decreased ratio of Bax/Bcl-2 caused by rotenone treatment. Additionally, rutin protected SH-SY5Y cells from rotenone-induced caspase-9 and caspase-3 activation and apoptotic cell death. We also observed that rutin repressed rotenone-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation. These results suggest that rutin may have therapeutic potential for the treatment of neurodegenerative diseases associated with oxidative stress.

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References

  1. Licker V, Kövari E, Hochstrasser DF, Burkhard PR (2009) Proteomics in human Parkinson’s disease research. J Proteomics 73:10–29

    Article  PubMed  CAS  Google Scholar 

  2. Thomas B, Beal MF (2007) Parkinson’s disease. Hum Mol Genet 16(R2):R183–R194

    Article  PubMed  CAS  Google Scholar 

  3. Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822

    Article  PubMed  CAS  Google Scholar 

  4. Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055

    Article  PubMed  Google Scholar 

  5. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR, Comyns K, Richards MB, Meng C, Priestley B, Fernandez HH, Cambi F, Umbach DM, Blair A, Sandler DP, Langston JW (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119:866–872

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87

    Article  PubMed  CAS  Google Scholar 

  7. Radad K, Rausch WD, Gille G (2006) Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem Int 49:379–386

    Article  PubMed  CAS  Google Scholar 

  8. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306

    Article  PubMed  CAS  Google Scholar 

  9. Alam M, Schmidt WJ (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136:317–324

    Article  PubMed  CAS  Google Scholar 

  10. Sherer TB, Richardson JR, Testa CM, Seo BB, Panov AV, Yagi T, Matsuno-Yagi A, Miller GW, Greenamyre JT (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 100:1469–1479

    PubMed  CAS  Google Scholar 

  11. Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 34:279–290

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Kim KH, Lee KW, Kim DY, Park HH, Kwon IB, Lee HJ (2005) Optimal recovery of high-purity rutin crystals from the whole plant of Fagopyrum esculentum Moench (buckwheat) by extraction, fractionation, and recrystallization. Bioresour Technol 96:1709–1712

    Article  PubMed  CAS  Google Scholar 

  13. Arau′jo JR, Gonc-alves P, Martel F (2011) Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. Nutr Res 31:77–87

    Article  CAS  Google Scholar 

  14. Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, Ashafaq M, Islam F, Siddiqui MS, Safhi MM, Islam F (2012) Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 210:340–352

    Article  PubMed  CAS  Google Scholar 

  15. Tongjaroenbuangam W, Ruksee N, Chantiratikul P, Pakdeenarong N, Kongbuntad W, Govitrapong P (2011) Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice. Neurochem Int 59:677–685

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. Wang SW, Wang YJ, Su YJ, Zhou WW, Yang SG, Zhang R, Zhao M, Li YN, Zhang ZP, Zhan DW, Liu RT (2012) Rutin inhibits β-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines. Neurotoxicology 33:482–490

    Article  PubMed  CAS  Google Scholar 

  18. Rodrigues AM, Marcilio Fdos S, Frazão Muzitano M, Giraldi-Guimarães A (2013) Therapeutic potential of treatment with the flavonoid rutin after cortical focal ischemia in rats. Brain Res 1503:53–61

    Article  PubMed  CAS  Google Scholar 

  19. Pu F, Mishima K, Irie K, Motohashi K, Tanaka Y, Orito K, Egawa T, Kitamura Y, Egashira N, Iwasaki K, Fujiwara M (2007) Neuroprotective effects of quercetin and rutin on spatial memory impairment in an 8-arm radial maze task and neuronal death induced by repeated cerebral ischemia in rats. J Pharmacol Sci 104:329–334

    Article  PubMed  CAS  Google Scholar 

  20. Koda T, Kuroda Y, Imai H (2009) Rutin supplementation in the diet has protective effects against toxicant-induced hippocampal injury by suppression of microglial activation and pro-inflammatory cytokines: protective effect of rutin against toxicant-induced hippocampal injury. Cell Mol Neurobiol 29:523–531

    Article  PubMed  CAS  Google Scholar 

  21. Nakayama M, Aihara M, Chen YN, Araie M, Tomita-Yokotani K, Iwashina T (2011) Neuroprotective effects of flavonoids on hypoxia-, glutamate-, and oxidative stress-induced retinal ganglion cell death. Mol Vis 17:1784–1793

    PubMed Central  PubMed  CAS  Google Scholar 

  22. Bae KH (2000) The Medicinal Plants of Korea. Kyo-Hak Publishing, Seoul, p 364

    Google Scholar 

  23. Yu HY, Kim KS, Lee YC, Moon HI, Lee JH (2012) Oleifolioside A, a new active compound, attenuates LPS-stimulated iNOS and COX-2 expression through the downregulation of NF-κB and MAPK activities in RAW 264.7 macrophages. Evid Based Complement Alternat Med 2012:637512. doi:10.1155/2012/637512

    PubMed Central  PubMed  Google Scholar 

  24. Yu HY, Jin CY, Kim KS, Lee YC, Park SH, Kim GY, Kim WJ, Moon HI, Choi YH, Lee JH (2012) Oleifolioside A mediates caspase-independent human cervical carcinoma HeLa cell apoptosis involving nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG. J Agric Food Chem 60:5400–5406

    Article  PubMed  CAS  Google Scholar 

  25. Park BY, Min BS, Oh SR, Kim JH, Kim TJ, Kim DH, Bae KH, Lee HK (2004) Isolation and anticomplement activity of compounds from Dendropanax morbifera. J Ethnopharmacol 90:403–408

    Article  PubMed  CAS  Google Scholar 

  26. Chung IM, Song HK, Kim SJ, Moon HI (2011) Anticomplement activity of polyacetylenes from leaves of Dendropanax morbifera Leveille. Phytother Res 25:784–786

    PubMed  CAS  Google Scholar 

  27. Chung IM, Kim MY, Park WH, Moon HI (2009) Antiatherogenic activity of Dendropanax morbifera essential oil in rats. Pharmazie 64:547–549

    PubMed  CAS  Google Scholar 

  28. Aoshima H, Satoh T, Sakai N, Yamada M, Enokido Y, Ikeuchi T, Hatanaka H (1997) Generation of free radicals during lipid hydroperoxide-triggered apoptosis in PC12 cells. Biochim Biophys Acta 1345:35–42

    Article  PubMed  CAS  Google Scholar 

  29. Freestone PS, Chung KK, Guatteo E, Mercuri NB, Nicholson LF, Lipski J (2009) Acute action of rotenone on nigral dopaminergic neurons—involvement of reactive oxygen species and disruption of Ca2+ homeostasis. Eur J Neurosci 30:1849–1859

    Article  PubMed  Google Scholar 

  30. Wang XJ, Xu JX (2005) Possible involvement of Ca2+ signaling in rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. Neurosci Lett 376:127–132

    Article  PubMed  CAS  Google Scholar 

  31. Newhouse K, Hsuan SL, Chang SH, Cai B, Wang Y, Xia Z (2004) Rotenone induced apoptosis is mediated by p38 and JNK MAP kinases in human dopaminergic SH-SY5Y cells. Toxicol Sci 79:137–146

    Article  PubMed  CAS  Google Scholar 

  32. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  PubMed  CAS  Google Scholar 

  33. Höglinger GU, Féger J, Prigent A, Michel PP, Parain K, Champy P, Ruberg M, Oertel WH, Hirsch EC (2003) Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem 84:491–502

    Article  PubMed  Google Scholar 

  34. Cabeza-Arvelaiz Y, Schiestl RH (2012) Transcriptome analysis of a rotenone model of parkinsonism reveals complex I-tied and -untied toxicity mechanisms common to neurodegenerative diseases. PLoS ONE 7:e44700. doi:10.1371/journal.pone.0044700

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Testa CM, Sherer TB, Greenamyre JT (2005) Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Res Mol Brain Res 134:109–118

    Article  PubMed  CAS  Google Scholar 

  36. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53:S26–S38

    Article  PubMed  CAS  Google Scholar 

  37. Panov A, Dikalov S, Shalbuyeva N, Taylor G, Sherer T, Greenamyre JT (2005) Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication. J Biol Chem 280:42026–42035

    Article  PubMed  CAS  Google Scholar 

  38. Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009332

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Cannon JR, Greenamyre JT (2011) The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci 124:225–250

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Schapira AH (1999) Science, medicine, and the future: Parkinson’s disease. BMJ 318:311–314

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. Berliocchi L, Bano D, Nicotera P (2005) Ca2þ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci 360:2255–2258

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Castillo MR, Babson JR (1998) Ca2+-dependent mechanisms of cell injury in cultured cortical neurons. Neuroscience 86:1133–1144

    Article  PubMed  CAS  Google Scholar 

  43. Kruman II, Mattson MP (1999) Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J Neurochem 72:529–540

    Article  PubMed  CAS  Google Scholar 

  44. Vila M, Przedborski S (2003) Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci 4:365–375

    Article  PubMed  CAS  Google Scholar 

  45. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  PubMed  CAS  Google Scholar 

  46. Sapkota K, Kim S, Park SE, Kim SJ (2011) Detoxified extract of Rhus verniciflua stokes inhibits rotenone-induced apoptosis in human dopaminergic cells, SH-SY5Y. Cell Mol Neurobiol 31:213–223

    Article  PubMed  Google Scholar 

  47. Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 23:599–622

    Article  PubMed  CAS  Google Scholar 

  48. Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E, Rice-Evans C (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23:861–880

    Article  PubMed  CAS  Google Scholar 

  49. Bendotti C, Tortarolo M, Borsello T (2006) Targeting stress activated protein kinases, JNK and p38, as new therapeutic approach for neurodegenerative diseases. Cent Nerv Syst Agents Med Chem 6:109–117

    Article  CAS  Google Scholar 

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Acknowledgments

This research was supported by Leaders in INdustry-university Cooperation (LINC) Project, Ministry of Education, Republic of Korea.

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Correspondence to Sung-Jun Kim or Seung Kim.

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Se-Eun Park and Kumar Sapkota have contributed equally to this study.

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Park, SE., Sapkota, K., Choi, JH. et al. 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 (2014). https://doi.org/10.1007/s11064-014-1259-5

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  • DOI: https://doi.org/10.1007/s11064-014-1259-5

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