Neurochemical Research

, Volume 33, Issue 5, pp 886–901 | Cite as

Dopamine Selectively Sensitizes Dopaminergic Neurons to Rotenone-Induced Apoptosis

  • Ferogh A. Ahmadi
  • Tom N. Grammatopoulos
  • Andy M. Poczobutt
  • Susan M. Jones
  • Laurence D. Snell
  • Mita Das
  • W. Michael Zawada
Original Paper

Abstract

Among various types of neurons affected in Parkinson’s disease, dopamine (DA) neurons of the substantia nigra undergo the most pronounced degeneration. Products of DA oxidation and consequent cellular damage have been hypothesized to contribute to neuronal death. To examine whether elevated intracellular DA will selectively predispose the dopaminergic subpopulation of nigral neurons to damage by an oxidative insult, we first cultured rat primary mesencephalic cells in the presence of rotenone to elevate reactive oxygen species. Although MAP2+ neurons were more sensitive to rotenone-induced toxicity than type 1 astrocytes, rotenone affected equally both DA (TH+) neurons and MAP2+ neurons. In contrast, when intracellular DA concentration was elevated, DA neurons became selectively sensitized to rotenone. Raising intracellular DA levels in primary DA neurons resulted in dopaminergic neuron death in the presence of subtoxic concentrations of rotenone. Furthermore, mitochondrial superoxide dismutase mimetic, manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, blocked activation of caspase-3, and consequent cell death. Our results demonstrate that an inhibitor of mitochondrial complex I and increased cytosolic DA may cooperatively lead to conditions of elevated oxidative stress and thereby promote selective demise of dopaminergic neurons.

Keywords

Parkinson’s disease Neurotoxin Dopaminergic Reactive oxygen species (ROS) Superoxide dismutase (SOD) mimetic Caspase-3 

References

  1. 1.
    Warner DS, Sheng H, Batinic-Haberle I (2004) Oxidants, antioxidants and the ischemic brain. J Exp Biol 207:3221–3231PubMedCrossRefGoogle Scholar
  2. 2.
    Jenner P, Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47:S161–S170PubMedGoogle Scholar
  3. 3.
    Sossi V, Fuente-Fernandez R, Holden JE, Doudet DJ, McKenzie J, Stoessl AJ, Ruth TJ (2002) Increase in dopamine turnover occurs early in Parkinson’s disease: evidence from a new modeling approach to PET 18F-fluorodopa data. J Cereb Blood Flow Metab 22:232–239PubMedCrossRefGoogle Scholar
  4. 4.
    Spina MB, Cohen G (1989) Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA 86:1398–1400PubMedCrossRefGoogle Scholar
  5. 5.
    Graham DG (1978) Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14:633–643PubMedGoogle Scholar
  6. 6.
    Sulzer D, Zecca L (2000) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1:181–195PubMedCrossRefGoogle Scholar
  7. 7.
    Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, Oya H, Ozawa T, Kagawa Y (1989) Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 163:1450–1455PubMedCrossRefGoogle Scholar
  8. 8.
    Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54:823–827PubMedCrossRefGoogle Scholar
  9. 9.
    Janetzky B, Hauck S, Youdim MB, Riederer P, Jellinger K, Pantucek F, Zochling R, Boissl KW, Reichmann H (1994) Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson’s disease. Neurosci Lett 169:126–128PubMedCrossRefGoogle Scholar
  10. 10.
    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 3:1301–1306PubMedCrossRefGoogle Scholar
  11. 11.
    Thiffault C, Langston JW, Di Monte DA (2000) Increased striatal dopamine turnover following acute administration of rotenone to mice. Brain Res 885:283–288PubMedCrossRefGoogle Scholar
  12. 12.
    Dunnett SB, Boulton AA, Baker GB (2000) Neural transplantation methods. Humana Press, TotowaGoogle Scholar
  13. 13.
    Szabo C, Day BJ, Salzman AL (1996) Evaluation of the relative contribution of nitric oxide and peroxynitrite to the suppression of mitochondrial respiration in immunostimulated macrophages using a manganese mesoporphyrin superoxide dismutase mimetic and peroxynitrite scavenger. FEBS Lett 381:82–86PubMedCrossRefGoogle Scholar
  14. 14.
    Ahmadi FA, Linseman DA, Grammatopoulos TN, Jones SM, Bouchard RJ, Freed CR, Heidenreich KA, Zawada WM (2003) The pesticide rotenone induces caspase-3-mediated apoptosis in ventral mesencephalic dopaminergic neurons. J Neurochem 87:914–921PubMedCrossRefGoogle Scholar
  15. 15.
    Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 179:9–16PubMedCrossRefGoogle Scholar
  16. 16.
    Liu Y, Edwards RH (1997) The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci 20:125–156PubMedCrossRefGoogle Scholar
  17. 17.
    Sipos I, Tretter L, Adam-Vizi V (2003) Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem 84:112–118PubMedCrossRefGoogle Scholar
  18. 18.
    Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316PubMedCrossRefGoogle Scholar
  19. 19.
    Rajput AH, Uitti RJ, Stern W, Laverty W, O’Donnell K, O’Donnell D, Yuen WK, Dua A (1987) Geography, drinking water chemistry, pesticides and herbicides and the etiology of Parkinson’s disease. Can J Neurol Sci 14:414–418PubMedGoogle Scholar
  20. 20.
    Ritz B, Yu F (2000) Parkinson’s disease mortality and pesticide exposure in California 1984–1994. Int J Epidemiol 29:323–329PubMedCrossRefGoogle Scholar
  21. 21.
    Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA (2000) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci 20:9207–9214PubMedGoogle Scholar
  22. 22.
    Bindoff LA, Birch-Machin M, Cartlidge NE, Parker WD Jr, Turnbull DM (1989) Mitochondrial function in Parkinson’s disease. Lancet 2:49PubMedCrossRefGoogle Scholar
  23. 23.
    Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 26:719–723PubMedCrossRefGoogle Scholar
  24. 24.
    Bindoff LA, Birch-Machin MA, Cartlidge NE, Parker WD Jr, Turnbull DM (1991) Respiratory chain abnormalities in skeletal muscle from patients with Parkinson’s disease. J Neurol Sci 104:203–208PubMedCrossRefGoogle Scholar
  25. 25.
    Tatton WG, Chalmers-Redman R, Brown D, Tatton N (2003) Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann Neurol 53(Suppl 3):S61–S70PubMedCrossRefGoogle Scholar
  26. 26.
    Obata T (2002) Role of hydroxyl radical formation in neurotoxicity as revealed by in vivo free radical trapping. Toxicol Lett 132:83–93PubMedCrossRefGoogle Scholar
  27. 27.
    Lee SY, Moon Y, Hee CD, Jin CH, Hwang O (2006) Particular vulnerability of rat mesencephalic dopaminergic neurons to tetrahydrobiopterin: relevance to Parkinson’s disease. Neurobiol Dis 25:112–120PubMedCrossRefGoogle Scholar
  28. 28.
    Mosharov EV, Staal RG, Bove J, Prou D, Hananiya A, Markov D, Poulsen N, Larsen KE, Moore CM, Troyer MD, Edwards RH, Przedborski S, Sulzer D (2006) Alpha-synuclein overexpression increases cytosolic catecholamine concentration. J Neurosci 26:9304–9311PubMedCrossRefGoogle Scholar
  29. 29.
    Mazzulli JR, Mishizen AJ, Giasson BI, Lynch DR, Thomas SA, Nakashima A, Nagatsu T, Ota A, Ischiropoulos H (2006) Cytosolic catechols inhibit alpha-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates. J Neurosci 26:10068–10078PubMedCrossRefGoogle Scholar
  30. 30.
    Hasbani DM, Perez FA, Palmiter RD, O’Malley KL (2005) Dopamine depletion does not protect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in vivo. J Neurosci 25:9428–9433PubMedCrossRefGoogle Scholar
  31. 31.
    Talpade DJ, Greene JG, Higgins DS Jr, Greenamyre JT (2000) In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem 75:2611–2621PubMedCrossRefGoogle Scholar
  32. 32.
    Verstreken P, Ly CV, Venken KJ, Koh TW, Zhou Y, Bellen HJ (2005) Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47:365–378PubMedCrossRefGoogle Scholar
  33. 33.
    Chee F, Mudher A, Newman TA, Cuttle M, Lovestone S, Shepherd D (2006) Overexpression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Biochem Soc Trans 34:88–90PubMedCrossRefGoogle Scholar
  34. 34.
    Hirsch EC, Hoglinger G, Rousselet E, Breidert T, Parain K, Feger J, Ruberg M, Prigent A, Cohen-Salmon C, Launay JM (2003) Animal models of Parkinson’s disease in rodents induced by toxins: an update. J Neural Transm Suppl 65:89–100PubMedGoogle Scholar
  35. 35.
    Zeevalk GD, Bernard LP (2005) Energy status, ubiquitin proteasomal function, and oxidative stress during chronic and acute complex I inhibition with rotenone in mesencephalic cultures. Antioxid Redox Signal 7:662–672PubMedCrossRefGoogle Scholar
  36. 36.
    Madhavan L, Ourednik V, Ourednik J (2006) Increased “vigilance” of antioxidant mechanisms in neural stem cells potentiates their capability to resist oxidative stress. Stem Cells 24:2110–2119PubMedCrossRefGoogle Scholar
  37. 37.
    Dukes AA, Korwek KM, Hastings TG (2005) The effect of endogenous dopamine in rotenone-induced toxicity in PC12 cells. Antioxid Redox Signal 7:630–638PubMedCrossRefGoogle Scholar
  38. 38.
    Liu HQ, Zhu XZ, Weng EQ (2005) Intracellular dopamine oxidation mediates rotenone-induced apoptosis in PC12 cells. Acta Pharmacol Sin 26:17–26PubMedCrossRefGoogle Scholar
  39. 39.
    Sakka N, Sawada H, Izumi Y, Kume T, Katsuki H, Kaneko S, Shimohama S, Akaike A (2003) Dopamine is involved in selectivity of dopaminergic neuronal death by rotenone. Neuroreport 14:2425–2428PubMedCrossRefGoogle Scholar
  40. 40.
    Santiago M, Granero L, Machado A, Cano J (1995) Complex I inhibitor effect on the nigral and striatal release of dopamine in the presence and absence of nomifensine. Eur J Pharmacol 280:251–256PubMedCrossRefGoogle Scholar
  41. 41.
    Bashkatova V, Alam M, Vanin A, Schmidt WJ (2004) Chronic administration of rotenone increases levels of nitric oxide and lipid peroxidation products in rat brain. Exp Neurol 186:235–241PubMedCrossRefGoogle Scholar
  42. 42.
    Segura-Aguilar J, Lind C (1989) On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine:prevention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase. Chem Biol Interact 72:309–324PubMedCrossRefGoogle Scholar
  43. 43.
    Daveu C, Servy C, Dendane M, Marin P, Ducrocq C (1997) Oxidation and nitration of catecholamines by nitrogen oxides derived from nitric oxide. Nitric Oxide 1:234–243PubMedCrossRefGoogle Scholar
  44. 44.
    Terland O, Flatmark T, Tangeras A, Gronberg M (1997) Dopamine oxidation generates an oxidative stress mediated by dopamine semiquinone and unrelated to reactive oxygen species. J Mol Cell Cardiol 29:1731–1738PubMedCrossRefGoogle Scholar
  45. 45.
    Seaton TA, Cooper JM, Schapira AH (1997) Free radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors. Brain Res 777:110–118PubMedCrossRefGoogle Scholar
  46. 46.
    Molina-Jimenez MF, Sanchez-Reus MI, Benedi J (2003) Effect of fraxetin and myricetin on rotenone-induced cytotoxicity in SH-SY5Y cells: comparison with N-acetylcysteine. Eur J Pharmacol 472:81–87PubMedCrossRefGoogle Scholar
  47. 47.
    Molina-Jimenez MF, Sanchez-Reus MI, Andres D, Cascales M, Benedi J (2004) Neuroprotective effect of fraxetin and myricetin against rotenone-induced apoptosis in neuroblastoma cells. Brain Res 1009:9–16PubMedCrossRefGoogle Scholar
  48. 48.
    Packer MA, Miesel R, Murphy MP (1996) Exposure to the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and nitric oxide simultaneously causes cyclosporin A-sensitive mitochondrial calcium efflux and depolarisation. Biochem Pharmacol 51:267–273PubMedCrossRefGoogle Scholar
  49. 49.
    He Y, Imam SZ, Dong Z, Jankovic J, Ali SF, Appel SH, Le W (2003) Role of nitric oxide in rotenone-induced nigro-striatal injury. J Neurochem 86:1338–1345PubMedCrossRefGoogle Scholar
  50. 50.
    Lin KT, Xue JY, Lin MC, Spokas EG, Sun FF, Wong PY (1998) Peroxynitrite induces apoptosis of HL-60 cells by activation of a caspase-3 family protease. Am J Physiol 274:C855–C860PubMedGoogle Scholar
  51. 51.
    Viriag L, Scott GS, Cuzzocrea S, Marmer D, Salzman AL, Szabo C (1998) Peroxynitrite-induced thymocyte apoptosis: the role of caspases and poly (ADP-ribose) synthetase (PARS) activation. Immunology 94:345–355CrossRefGoogle Scholar
  52. 52.
    Bolanos JP, Peuchen S, Heales SJ, Land JM, Clark JB (1994) Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J Neurochem 63:910–916PubMedCrossRefGoogle Scholar
  53. 53.
    Cassina A, Radi R (1996) Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 328:309–316PubMedCrossRefGoogle Scholar
  54. 54.
    LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484–1491PubMedGoogle Scholar
  55. 55.
    LaVoie MJ, Hastings TG (1999) Peroxynitrite- and nitrite-induced oxidation of dopamine: implications for nitric oxide in dopaminergic cell loss. J Neurochem 73:2546–2554PubMedCrossRefGoogle Scholar
  56. 56.
    Imam SZ, Newport GD, Itzhak Y, Cadet JL, Islam F, Slikker W Jr, Ali SF (2001) Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase. J Neurochem 76:745–749PubMedCrossRefGoogle Scholar
  57. 57.
    Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti RR, Horwitz J, Ischiropoulos H (1998) Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci USA 95:7659–7663PubMedCrossRefGoogle Scholar
  58. 58.
    Schulz JB, Matthews RT, Muqit MM, Browne SE, Beal MF (1995) Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. J Neurochem 64:936–939PubMedCrossRefGoogle Scholar
  59. 59.
    Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med 2:1017–1021PubMedCrossRefGoogle Scholar
  60. 60.
    Boireau A, Dubedat P, Bordier F, Imperato A, Moussaoui S (2000) The protective effect of riluzole in the MPTP model of Parkinson’s disease in mice is not due to a decrease in MPP(+) accumulation. Neuropharmacology 39:1016–1020PubMedCrossRefGoogle Scholar
  61. 61.
    Yamada T, McGeer PL, Baimbridge KG, McGeer EG (1990) Relative sparing in Parkinson’s disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res 526:303–307PubMedCrossRefGoogle Scholar
  62. 62.
    German DC, Manaye KF, Sonsalla PK, Brooks BA (1992) Midbrain dopaminergic cell loss in Parkinson’s disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells. Ann N Y Acad Sci 648:42–62PubMedCrossRefGoogle Scholar
  63. 63.
    Meyer M, Zimmer J, Seiler RW, Widmer HR (1999) GDNF increases the density of cells containing calbindin but not of cells containing calretinin in cultured rat and human fetal nigral tissue. Cell Transplant 8:25–36PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ferogh A. Ahmadi
    • 1
    • 2
  • Tom N. Grammatopoulos
    • 1
    • 3
  • Andy M. Poczobutt
    • 1
  • Susan M. Jones
    • 1
  • Laurence D. Snell
    • 3
  • Mita Das
    • 1
  • W. Michael Zawada
    • 1
    • 2
    • 4
  1. 1.Division of Clinical Pharmacology and Toxicology, Department of MedicineUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  2. 2.Neuroscience ProgramUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  3. 3.Department of PharmacologyUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  4. 4.Division of Clinical Pharmacology, C-237University of Colorado at Denver and Health Sciences CenterDenverUSA

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