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Protective Effects of Salidroside in the MPTP/MPP+-Induced Model of Parkinson's Disease through ROS–NO-Related Mitochondrion Pathway

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Abstract

Parkinson's disease is a progressive neurodegenerative disease causing tremor, rigidity, bradykinesia, and gait impairment. Oxidative stress and mitochondrial dysfunction play important roles in the development of Parkinson disease. Salidroside (Sal), a phenylpropanoid glycoside isolated from Rhodiola rosea L., has potent antioxidant properties. Previous work from our group suggests that Sal might protect dopaminergic neurons through inhibition of reactive oxygen species (ROS) and nitric oxide (NO) generation. In the present study, we investigated the protective effects of Sal in MPTP/MPP+ models of Parkinson's disease in an attempt to elucidate the underlying mechanism of protection. We found that Sal pretreatment protected dopaminergic neurons against MPTP/MPP+-induced toxicity in a dose-dependent manner by: (1) reducing the production of ROS–NO, (2) regulating the ratio of Bcl-2/Bax, (3) decreasing cytochrome-c and Smac release, and inhibiting caspase-3, caspas-6, and caspas-9 activation, and (4) reducing α-synuclein aggregation. The present study supports the hypothesis that Sal may act as an effective neuroprotective agent through modulation of the ROS–NO-related mitochondrial pathway in vitro and in vivo.

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Reference

  1. de Lau LM, Breteler MM (2006) Epidemiology of Parkinson's disease. Lancet Neurol 5(6):525–535

    Article  PubMed  Google Scholar 

  2. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ (2002) The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125(Pt 4):861–870

    Article  PubMed  Google Scholar 

  3. Meissner W, Hill MP, Tison F, Gross CE, Bezard E (2004) Neuroprotective strategies for Parkinson's disease: conceptual limits of animal models and clinical trials. Trends Pharmacol Sci 25(5):249–253

    Article  CAS  PubMed  Google Scholar 

  4. Foltynie T, Kahan J (2013) Parkinson's disease: an update on pathogenesis and treatment. J Neurol 260(5):1433–1440

    Article  CAS  PubMed  Google Scholar 

  5. Shukla V, Mishra SK, Pant HC (2011) Oxidative stress in neurodegeneration. Adv Pharmacol Sci 2011:572634

    PubMed Central  PubMed  Google Scholar 

  6. Martinez TN, Greenamyre JT (2012) Toxin models of mitochondrial dysfunction in Parkinson's disease. Antioxid Redox Signal 16(9):920–934

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schule B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S (2013) Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342(6161):983–987

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases. Mol Cell Neurosci 55:101–114

    Article  CAS  PubMed  Google Scholar 

  9. Beal MF (2009) Therapeutic approaches to mitochondrial dysfunction in Parkinson's disease. Parkinsonism Relat Disord 15(Suppl 3):S189–S194

    Article  PubMed  Google Scholar 

  10. Guo S, Bezard E, Zhao B (2005) Protective effect of green tea polyphenols on the SH-SY5Y cells against 6-OHDA induced apoptosis through ROS-NO pathway. Free Radic Biol Med 39(5):682–695

    Article  CAS  PubMed  Google Scholar 

  11. Sheng QS, Wang ZJ, Zhang J, Zhang YG (2013) Salidroside promotes peripheral nerve regeneration following crush injury to the sciatic nerve in rats. Neuroreport 24(5):217–223

    Article  PubMed  Google Scholar 

  12. Yin D, Yao W, Chen S, Hu R, Gao X (2009) Salidroside, the main active compound of Rhodiola plants, inhibits high glucose-induced mesangial cell proliferation. Planta Med 75(11):1191–1195

    Article  CAS  PubMed  Google Scholar 

  13. Zhang L, Yu H, Sun Y, Lin X, Chen B, Tan C, Cao G, Wang Z (2007) Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol 564(1–3):18–25

    CAS  PubMed  Google Scholar 

  14. Chen X, Liu J, Gu X, Ding F (2008) Salidroside attenuates glutamate-induced apoptotic cell death in primary cultured hippocampal neurons of rats. Brain Res 1238:189–198

    Article  CAS  PubMed  Google Scholar 

  15. Cao LL, Du GH, Wang MW (2006) The effect of salidroside on cell damage induced by glutamate and intracellular free calcium in PC12 cells. J Asian Nat Prod Res 8(1–2):159–165

    Article  CAS  PubMed  Google Scholar 

  16. Li X, Ye X, Li X, Sun X, Liang Q, Tao L, Kang X, Chen J (2011) Salidroside protects against MPP(+)-induced apoptosis in PC12 cells by inhibiting the NO pathway. Brain Res 1382:9–18

    Article  CAS  PubMed  Google Scholar 

  17. Tatton WG, Chalmers-Redman RM, Ju WJ, Mammen M, Carlile GW, Pong AW, Tatton NA (2002) Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells. J Pharmacol Exp Ther 301(2):753–764

    Article  CAS  PubMed  Google Scholar 

  18. Ormerod MG, Collins MK, Rodriguez-Tarduchy G, Robertson D (1992) Apoptosis in interleukin-3-dependent haemopoietic cells. Quantification by two flow cytometric methods. J Immunol Methods 153(1–2):57–65

    Article  CAS  PubMed  Google Scholar 

  19. Myhre O, Andersen JM, Aarnes H, Fonnum F (2003) Evaluation of the probes 2',7'-dichlorofluorescin diacetate, luminol, and lucigenin as indicators of reactive species formation. Biochem Pharmacol 65(10):1575–1582

    Article  CAS  PubMed  Google Scholar 

  20. Kojima H, Urano Y, Kikuchi K, Higuchi T, Hirata Y, Nagano T (1999) Fluorescent indicators for imaging nitric oxide production. Angew Chem Int Ed Engl 38(21):3209–3212

    Article  CAS  PubMed  Google Scholar 

  21. Matsuura K, Kabuto H, Makino H, Ogawa N (1997) Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods 73(1):45–48

    Article  CAS  PubMed  Google Scholar 

  22. Wang W, Yang Y, Ying C, Li W, Ruan H, Zhu X, You Y, Han Y, Chen R, Wang Y, Li M (2007) Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity. Neuropharmacology 52(8):1678–1684

    Article  CAS  PubMed  Google Scholar 

  23. Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S (1995) Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 4(3):257–269

    Article  CAS  PubMed  Google Scholar 

  24. Sriram K, Pai KS, Boyd MR, Ravindranath V (1997) Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res 749(1):44–52

    Article  CAS  PubMed  Google Scholar 

  25. Grunblatt E, Mandel S, Youdim MB (2000) MPTP and 6-hydroxydopamine-induced neurodegeneration as models for Parkinson's disease: neuroprotective strategies. J Neurol 247(Suppl 2):I95–I102

    Google Scholar 

  26. Przedborski S, Vila M (2003) The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease. Ann N Y Acad Sci 991:189–198

    Article  CAS  PubMed  Google Scholar 

  27. Przedborski S, Jackson-Lewis V, Djaldetti R, Liberatore G, Vila M, Vukosavic S, Almer G (2000) The parkinsonian toxin MPTP: action and mechanism. Restor Neurol Neurosci 16(2):135–142

    CAS  PubMed  Google Scholar 

  28. Marsden CD (1990) Parkinson's disease. Lancet 335(8695):948–952

    Article  CAS  PubMed  Google Scholar 

  29. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20(4):415–455

    Article  CAS  PubMed  Google Scholar 

  30. Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in parkinson's disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38(3–4):277–301

    Article  CAS  PubMed  Google Scholar 

  31. Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease. J Neurosci 21(17):6853–6861

    CAS  PubMed  Google Scholar 

  32. Kasprzak KS (2002) Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis. Free Radic Biol Med 32(10):958–967

    Article  CAS  PubMed  Google Scholar 

  33. Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12(10):1161–1208

    Article  CAS  PubMed  Google Scholar 

  34. Stadtman ER (1992) Protein oxidation and aging. Science 257(5074):1220–1224

    Article  CAS  PubMed  Google Scholar 

  35. Maguire-Zeiss KA, Short DW, Federoff HJ (2005) Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson's disease? Brain Res Mol Brain Res 134(1):18–23

    Article  CAS  PubMed  Google Scholar 

  36. Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 52(2):381–389

    Article  CAS  PubMed  Google Scholar 

  37. Brieger K, Schiavone S, Miller FJ, Krause KH (2012) Reactive oxygen species: from health to disease. Swiss Med Wkly 142:w13659

    CAS  PubMed  Google Scholar 

  38. Patten DA, Germain M, Kelly MA, Slack RS (2010) Reactive oxygen species: stuck in the middle of neurodegeneration. J Alzheimers Dis 20(Suppl 2):S357–S367

    PubMed  Google Scholar 

  39. Di Monte D, Sandy MS, Ekstrom G, Smith MT (1986) Comparative studies on the mechanisms of paraquat and 1-methyl-4-phenylpyridine (MPP+) cytotoxicity. Biochem Biophys Res Commun 137(1):303–309

    Article  PubMed  Google Scholar 

  40. Kern JC, Kehrer JP (2005) Free radicals and apoptosis: relationships with glutathione, thioredoxin, and the BCL family of proteins. Front Biosci 10:1727–1738

    Article  CAS  PubMed  Google Scholar 

  41. Cassarino DS, Parks JK, Parker WJ, Bennett JJ (1999) The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453(1):49–62

    Article  CAS  PubMed  Google Scholar 

  42. Calabrese V, Cornelius C, Rizzarelli E, Owen JB, Dinkova-Kostova AT, Butterfield DA (2009) Nitric oxide in cell survival: a Janus molecule. Antioxid Redox Signal 11(11):2717–2739

    Article  CAS  PubMed  Google Scholar 

  43. Del-Bel E, Padovan-Neto FE, Raisman-Vozari R, Lazzarini M (2011) Role of nitric oxide in motor control: implications for Parkinson's disease pathophysiology and treatment. Curr Pharm Des 17(5):471–488

    Article  CAS  PubMed  Google Scholar 

  44. Dawson VL, Dawson TM (1998) Nitric oxide in neurodegeneration. Prog Brain Res 118:215–229

    Article  CAS  PubMed  Google Scholar 

  45. Zhang L, Dawson VL, Dawson TM (2006) Role of nitric oxide in Parkinson's disease. Pharmacol Ther 109(1–2):33–41

    Article  CAS  PubMed  Google Scholar 

  46. Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL, Dawson TM (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci U S A 93(10):4565–4571

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5(12):1403–1409

    Article  CAS  PubMed  Google Scholar 

  48. Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL, Dawson TM (1999) Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci U S A 96(10):5774–5779

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Schmitt K, Grimm A, Kazmierczak A, Strosznajder JB, Gotz J, Eckert A (2012) Insights into mitochondrial dysfunction: aging, amyloid-beta, and tau-A deleterious trio. Antioxid Redox Signal 16(12):1456–1466

    Article  CAS  PubMed  Google Scholar 

  50. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87(1):99–163

    Article  CAS  PubMed  Google Scholar 

  51. Schapira AH (2006) Mitochondrial disease. Lancet 368(9529):70–82

    Article  CAS  PubMed  Google Scholar 

  52. Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183

    Article  CAS  PubMed  Google Scholar 

  53. Du L, Mei HF, Yin X, Xing YQ (2014) Delayed growth of glioma by a polysaccharide from Aster tataricus involve upregulation of Bax/Bcl-2 ratio, activation of caspase-3/8/9, and downregulation of the Akt. Tumour Biol 35:1819–1825

  54. Graham RK, Ehrnhoefer DE, Hayden MR (2011) Caspase-6 and neurodegeneration. Trends Neurosci 34(12):646–656

    Article  CAS  PubMed  Google Scholar 

  55. Chu Y, Mickiewicz AL, Kordower JH (2011) alpha-Synuclein aggregation reduces nigral myocyte enhancer factor-2D in idiopathic and experimental Parkinson's disease. Neurobiol Dis 41(1):71–82

    Article  CAS  PubMed  Google Scholar 

  56. Adamczyk A, Kazmierczak A, Strosznajder JB (2006) alpha-Synuclein and its neurotoxic fragment inhibit dopamine uptake into rat striatal synaptosomes. Relationship to nitric oxide. Neurochem Int 49(4):407–412

    Article  CAS  PubMed  Google Scholar 

  57. Tsang AH, Chung KK (2009) Oxidative and nitrosative stress in Parkinson's disease. Biochim Biophys Acta 1792(7):643–650

    Article  CAS  PubMed  Google Scholar 

  58. Chu Y, Mickiewicz AL, Kordower JH (2011) alpha-Synuclein aggregation reduces nigral myocyte enhancer factor-2D in idiopathic and experimental Parkinson's disease. Neurobiol Dis 41(1):71–82

    Article  CAS  PubMed  Google Scholar 

  59. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2009) alpha-Synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int J Biochem Cell Biol 41(10):2015–2024

    Article  CAS  PubMed  Google Scholar 

  60. Singh S, Dikshit M (2007) Apoptotic neuronal death in Parkinson's disease: involvement of nitric oxide. Brain Res Rev 54(2):233–250

    Article  CAS  PubMed  Google Scholar 

  61. Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P (2004) alpha-Synuclein and Parkinson's disease. FASEB J 18(6):617–626

    Article  CAS  PubMed  Google Scholar 

  62. Przedborski S, Chen Q, Vila M, Giasson BI, Djaldatti R, Vukosavic S, Souza JM, Jackson-Lewis V, Lee VM, Ischiropoulos H (2001) Oxidative post-translational modifications of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. J Neurochem 76(2):637–640

    Article  CAS  PubMed  Google Scholar 

  63. Maguire-Zeiss KA (2008) alpha-Synuclein: a therapeutic target for Parkinson's disease? Pharmacol Res 58(5–6):271–280

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by grants from the Nature Science Foundation of China (Project No. 81173590).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Research Center of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, 169 West Changle Road, Xi’an, 710032, People’s Republic of China

    Songhai Wang, Hong He, Wei Zhang & Jianzong Chen

  2. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi’an, 710038, People’s Republic of China

    Lei Chen

  3. Department of Physics and Mathematics, Fourth Military Medical University, 169 West Changle Road, Xi’an, 710032, People’s Republic of China

    Xiaojun Zhang

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  1. Songhai Wang
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  2. Hong He
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  4. Wei Zhang
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Correspondence to Xiaojun Zhang or Jianzong Chen.

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The authors Songhai Wang and Hong He contributed equally to this work.

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Wang, S., He, H., Chen, L. et al. Protective Effects of Salidroside in the MPTP/MPP+-Induced Model of Parkinson's Disease through ROS–NO-Related Mitochondrion Pathway. Mol Neurobiol 51, 718–728 (2015). https://doi.org/10.1007/s12035-014-8755-0

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