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.
Similar content being viewed by others
References
Licker V, Kövari E, Hochstrasser DF, Burkhard PR (2009) Proteomics in human Parkinson’s disease research. J Proteomics 73:10–29
Thomas B, Beal MF (2007) Parkinson’s disease. Hum Mol Genet 16(R2):R183–R194
Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822
Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055
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
Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87
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
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
Alam M, Schmidt WJ (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136:317–324
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
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
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
Arau′jo JR, Gonc-alves P, Martel F (2011) Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. Nutr Res 31:77–87
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
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
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
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
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
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
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
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
Bae KH (2000) The Medicinal Plants of Korea. Kyo-Hak Publishing, Seoul, p 364
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
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
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
Chung IM, Song HK, Kim SJ, Moon HI (2011) Anticomplement activity of polyacetylenes from leaves of Dendropanax morbifera Leveille. Phytother Res 25:784–786
Chung IM, Kim MY, Park WH, Moon HI (2009) Antiatherogenic activity of Dendropanax morbifera essential oil in rats. Pharmazie 64:547–549
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
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
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
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
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795
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
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
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
Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53:S26–S38
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
Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009332
Cannon JR, Greenamyre JT (2011) The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci 124:225–250
Schapira AH (1999) Science, medicine, and the future: Parkinson’s disease. BMJ 318:311–314
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
Castillo MR, Babson JR (1998) Ca2+-dependent mechanisms of cell injury in cultured cortical neurons. Neuroscience 86:1133–1144
Kruman II, Mattson MP (1999) Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J Neurochem 72:529–540
Vila M, Przedborski S (2003) Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci 4:365–375
Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776
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
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
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
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
Acknowledgments
This research was supported by Leaders in INdustry-university Cooperation (LINC) Project, Ministry of Education, Republic of Korea.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Se-Eun Park and Kumar Sapkota have contributed equally to this study.
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-014-1259-5