Skip to main content
SpringerLink
Log in

MPP+

Mechanism for its toxicity in cerebellar granule cells

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Cerebellar granule cells constitute the largest homogeneous neuronal population of the mammalian brain. However, they are not often used in studies that involve MPP+-neurotoxicity. Currently, it is known that the toxicity of MPP+ in cerebellar granule cells as well as in other models, including dopaminergic cells, results from activation of the apoptotic machinery after an initial oxidative burst with mitochondrial damage and energetic failure. Therefore, cerebellar granule cells serve as a good model to investigate the MPP+ effects and to study in vitro the molecular mechanism implicated in the genesis of Parkinson’s disease.

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

Similar content being viewed by others

References

  1. Gallo V., Ciotti M. T., Coletti A., Aloisi F., and Levi G. (1982) Selective release of glutamate from cerebellar granule cells differentiating in culture. Proc. Natl. Acad. Sci. USA 79, 7919–7923.

    Article  PubMed  CAS  Google Scholar 

  2. Kingsbury A. E., Gallo V., Woodhams P. L., and Balazs R. (1985) Survival, morphology and adhesion properties of cerebellar interneurones cultured in chemically defined and serum-supplemented medium. Brain Res. 349, 17–25.

    PubMed  CAS  Google Scholar 

  3. Thangnipon W., Kingsbury A., Webb M., and Balazs R., Observations on rat cerebellar cells in vitro: influence of substratum, potassium concentration and relationship between neurones and astrocytes. Brain Res. 313, (1983) 177–189.

    PubMed  CAS  Google Scholar 

  4. Marini A. M., Schwartz J. P., and Kopin I. J. (1989) The neurotoxicity of 1-methyl-4-phenylpyridinium in cultured cerebellar granule cells. J. Neurosci. 9, 3665–3672.

    PubMed  CAS  Google Scholar 

  5. Dipasquale B., Marini A. M., and Youle R. J. (1991) Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. Biochem. Biophys. Res. Commun. 181, 1442–1448.

    Article  PubMed  CAS  Google Scholar 

  6. Du Y., Dodel R. C., Bales K. R., Jemmerson R., Hamilton-Byrd E., and Paul S. M. (1997) Involvement of a caspase-3-like cysteine protease in 1-methyl-4-phenylpyridinium-mediated apoptosis of cultured cerebellar granule neurons, J. Neurochem. 69, 1382–1388.

    Article  PubMed  CAS  Google Scholar 

  7. Gonzalez-Polo R. A., Mora A., Clemente N., et al. (2001) Mechanisms of MPP(+) incorporation into cerebellar granule cells. Brain Res. Bull. 56, 119–123.

    Article  PubMed  CAS  Google Scholar 

  8. Gonzalez-Polo R. A., Soler G., Alvarez A., Fabregat I., and Fuentes J. M. (2003) Vitamin E blocks early events induced by 1-methyl-4-phenylpyridinium (MPP+) in cerebellar granule cells. J. Neurochem. 84, 305–315.

    Article  PubMed  CAS  Google Scholar 

  9. Takada M., Campbell K. J., and Hattori T. (1991) Regional localization of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) uptake: mismatch between its uptake and neurotoxic sites. Neurosci. Lett. 133, 137–140.

    Article  PubMed  CAS  Google Scholar 

  10. Lossi L. and Merighi A. (2003) In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS. Prog. Neurobiol. 69, 287–312.

    Article  PubMed  CAS  Google Scholar 

  11. Clarke P. G. (1990) Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. (Berl). 181, 195–213.

    CAS  Google Scholar 

  12. Cohen I., Castedo M., and Kroemer G. (2002) Tantalizing Thanatos: unexpected links in death pathways. Trends Cell Biol. 12, 293–295.

    Article  PubMed  CAS  Google Scholar 

  13. Kerr J. F., Wyllie A. H., and Currie A. R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257.

    PubMed  CAS  Google Scholar 

  14. Boobis A. R., Fawthrop D. J., and Davies D. S. (1990) Mechanisms of cell toxicity. Curr. Opin. Cell Biol. 2, 231–237.

    Article  PubMed  CAS  Google Scholar 

  15. Stewart B. W. (1994) Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators. J. Natl. Cancer Inst. 86, 1286–1296.

    Article  PubMed  CAS  Google Scholar 

  16. Ortiz A., Lorz C., Justo P., Catalan M. P., and Egido J. (2001) Contribution of apoptotic cell death to renal injury. J. Cell Mol. Med. 5, 18–32.

    Article  PubMed  CAS  Google Scholar 

  17. Marks N. and Berg M. J. (1999) Recent advances on neuronal caspases in development and neurodegeneration. Neurochem. Int. 35, 195–220.

    Article  PubMed  CAS  Google Scholar 

  18. Eberhardt O. and Schulz J. B. (2003) Apoptotic mechanisms and antiapoptotic therapy in the MPTP model of Parkinson’s disease. Toxicol. Lett. 139, 135–151.

    Article  PubMed  CAS  Google Scholar 

  19. Ferri K. F. and Kroemer G. (2001) Organelle-specific initiation of cell death pathways, Nat. Cell Biol. 3, E255-E263.

    Article  PubMed  CAS  Google Scholar 

  20. Zakeri Z. and Lockshin R. A. (2002) Cell death during development. J. Immunol. Methods 265, 3–20.

    Article  PubMed  CAS  Google Scholar 

  21. Langston J. W., Ballard P., Tetrud J. W., and Irwin I. (1983) Chronic Pakinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980.

    Article  PubMed  CAS  Google Scholar 

  22. Davis G. C., Williams A. C., Markey S. P., et al. (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res. 1, 249–254.

    Article  PubMed  CAS  Google Scholar 

  23. Chiueh C. C., Huang S. J., and Murphy D. L. (1992) Enhanced hydroxyl radical generation by 2′-methyl analog of MPTP: suppression by clorgyline and deprenyl. Synapse 11, 346–348.

    Article  PubMed  CAS  Google Scholar 

  24. Chiueh C. C., Miyake H., and Peng M. T. (1993) Role of dopamine autoxidation, hydroxyl radical generation, and calcium overload in underlying mechanisms involved in MPTP-induced parkinsonism. Adv. Neurol. 60, 251–258.

    PubMed  CAS  Google Scholar 

  25. Heikkila R. E., Nicklas W. J., Vyas I., and Duvoisin R. C. (1985) Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci. Lett. 62, 389–394.

    Article  PubMed  CAS  Google Scholar 

  26. Hartley A., Stone J. M., Heron C., Cooper J. M., and Schapira A. H. (1994) Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: relevance to Parkinson’s disease. J. Neurochem. 63, 1987–1990.

    Article  PubMed  CAS  Google Scholar 

  27. Mochizuki H., Nakamura N., Nishi K., and Mizuno Y. (1994) Apoptosis is induced by 1-methyl-4-phenylpyridinium ion (MPP+) in ventral mesencephalic-striatal coculture in rat. Neurosci. Lett. 170, 191–194.

    Article  PubMed  CAS  Google Scholar 

  28. Itano Y. and Nomura Y. (1995) 1-methyl-4-phenyl-pyridinium ion (MPP+) causes DNA fragmentation and increases the Bcl-2 expression in human neuroblastoma, SH-SY5Y cells, through different mechanisms. Brain Res. 704, 240–245.

    Article  PubMed  CAS  Google Scholar 

  29. Yoshinaga N., Murayama T., and Nomura Y. (2000) Apoptosis induction by a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), and inhibition by epidermal growth factor in GH3 cells. Biochem. Pharmacol. 60, 111–120.

    Article  PubMed  CAS  Google Scholar 

  30. Nicotra A. and Parvez S. H. (2000) Cell death induced by MPTP, a substrate for monoamine oxidase B. Toxicology 153, 157–166.

    Article  CAS  Google Scholar 

  31. Leist M., Volbracht C., Fava E., and Nicotera P. (1998) 1-Methyl-4-phenylpyridinium induces autocrine excitotoxicity, protease activation, and neuronal apoptosis. Mol. Pharmacol. 54, 789–801.

    PubMed  CAS  Google Scholar 

  32. Camins A., Sureda F. X., Gabriel C., Pallas M., Escubedo E., and Camarasa J. (1997) Effect of 1-methyl-4-phenylpyridinium (MPP+) on mitochondrial membrane potential in cerebellar neurons: interaction with the NMDA receptor. J. Neural. Transm 104, 569–577.

    Article  PubMed  CAS  Google Scholar 

  33. Tipton K. F. and Singer T. P. (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J. Neurochem. 61, 1191–1206.

    Article  PubMed  CAS  Google Scholar 

  34. Mayer R. A., Kindt M. V., and Heikkila R. E. (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J. Neurochem. 47, 1073–1079.

    Article  PubMed  CAS  Google Scholar 

  35. Bougria M., Vitorica J., Cano J., and Machado A. (1995) Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes. Eur. J. Pharmacol. 291, 407–415.

    Article  PubMed  CAS  Google Scholar 

  36. Snape B. M., Pileblad E., Ekman A., Magnusson T., Carlsson A., and Engel J. (1988) The effects of 1-methyl-4-phenylpyridinium ion (MPP+) on the efflux and metabolism of endogenous dopamine in rat striatal slices. J. Pharm. Pharmacol. 40, 620–626.

    PubMed  CAS  Google Scholar 

  37. Shang T., Uihlein A. V., Van Asten J., Kalyanaraman B., and Hillard C. J. (2003) 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J. Neurochem. 85, 358–367.

    PubMed  CAS  Google Scholar 

  38. Reinhard J. F., Jr. Daniels A. J., and Painter G. R. (1990) Carrier-independent entry of 1-methyl-4-phenylpyridinium (MPP+) into adrenal chromaffin cells as a consequence of charge delocalization. Biochem. Biophys. Res. Commun. 168, 1143–1148.

    Article  PubMed  CAS  Google Scholar 

  39. Kitamura Y., Kosaka T., Kakimura J. I., et al. (1998) Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl-4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells. Mol. Pharmacol. 54, 1046–1054.

    PubMed  CAS  Google Scholar 

  40. Desole M. S., Esposito G., Enrico P., et al. (1993) Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat. Neurosci. Lett. 159, 143–146.

    Article  PubMed  CAS  Google Scholar 

  41. Rossetti Z. L., Sotgiu A., Sharp D. E. Hadjiconstantinou M., and Neff N. H. (1988) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro. Biochem. Pharmacol. 37, 4573–4574.

    Article  PubMed  CAS  Google Scholar 

  42. Gonzalez-Polo R. A., Soler G., Alvarez A., Fabregat I., and Fuentes J. M. (2003) Vitamin E blocks early events induced by 1-methyl-4-phenylpyridinium (MPP+) in cerebellar granule cells. J. Neurochem. 84, 305–315.

    Article  PubMed  CAS  Google Scholar 

  43. Kalivendi S. V., Kotamraju S., Cunningham S., Shang T., Hillard C. J., and Kalyanaraman B. (2003) 1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. Biochem. J. 371, 151–164.

    Article  PubMed  CAS  Google Scholar 

  44. Gonzalez-Polo R. A., Soler G., Alonso J. C., Rodriguez-Martin A., and Fuentes J. M. (2004) Protection by antioxidants in MPP+ neurotoxicity in cerebellar granule cells. Cell Biology International, in press.

  45. Atlante A., Gagliardi S., Minervini G. M., Ciotti M. T., Marra E., and Calissano P. (1997) Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation. J. Neurochem. 68, 2038–2045.

    Article  PubMed  CAS  Google Scholar 

  46. Satoh T., Numakawa T., Abiru Y., et al. (1998) Production of reactive oxygen species and release of l-glutamate during superoxide anioninduced cell death of cerebellar granule neurons. J. Neurochem. 70, 316–324.

    Article  PubMed  CAS  Google Scholar 

  47. Valencia A. and Moran J. (2004) Reactive oxygen species induce different cell death mechanisms in cultured neurons. Free Radic. Biol. Med. 36, 1112–1125.

    Article  PubMed  CAS  Google Scholar 

  48. Atlante A., Gagliardi S., Minervini G. M., Ciotti M. T., Marra E., and Calissano P. (1997) Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation. J. Neurochem. 68, 2038–2045.

    Article  PubMed  CAS  Google Scholar 

  49. Akaneya Y., Takahashi M., and Hatanaka H. (1995) Involvement of free radicals in MPP+ neurotoxicity against rat dopaminergic neurons in culture. Neurosci. Lett. 193, 53–56.

    Article  PubMed  CAS  Google Scholar 

  50. Cassarino D. S., Fall C. P., Swerdlow R. H., et al. (1997) Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson’s disease. Biochim. Biophys. Acta. 1362, 77–86.

    PubMed  CAS  Google Scholar 

  51. Ben Shachar D. and Youdim M. B. (1993) Iron, melanin and dopamine interaction: relevance to Parkinson’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 17, 139–150.

    Article  PubMed  CAS  Google Scholar 

  52. Santiago M., Matarredona E. R., Granero L., Cano J., and Machado A. (1997) Neuroprotective effect of the iron chelator desferrioxamine against MPP+ toxicity on striatal dopaminergic terminals. J. Neurochem. 68, 732–738.

    Article  PubMed  CAS  Google Scholar 

  53. Beckman J. S., Beckman T. W., Chen J., Marshall P. A., and Freeman B. A. (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA 87, 1620–1624.

    Article  PubMed  CAS  Google Scholar 

  54. Misko T. P., Highkin M. K., Veenhuizen A. W., et al. (1998) Characterization of the cytoprotective action of peroxynitrite decomposition catalysts. J. Biol. Chem. 273, 15,646–15,653.

    Article  CAS  Google Scholar 

  55. Przedborski S., Jackson-Lewis V., Yokoyama R., Shibata T., Dawson V. L., and Dawson T. M. (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc. Natl. Acad. Sci. USA 93, 4565–4571.

    Article  PubMed  CAS  Google Scholar 

  56. Schulz J. B., Matthews R. T., Muqit M. M., Browne S. E., and Beal M. F. (1995) Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. J. Neurochem. 64, 936–939.

    Article  PubMed  CAS  Google Scholar 

  57. Hantraye P., Brouillet E., Ferrante R., et al. (1996) Beal M. F., Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat. Med. 2, 1017–1021.

    Article  PubMed  CAS  Google Scholar 

  58. Simmons M. L. and Murphy S. (1993) Cytokines regulate l-arginine-dependent cyclic GMP production in rat glial cells. Eur. J. Neurosci. 5, 825–831.

    Article  PubMed  CAS  Google Scholar 

  59. Przedborski S., Jackson-Lewis V., Djaldetti R., et al. (2000) The parkinsonian toxin MPTP: action and mechanism. Restor. Neurol. Neurosci. 16, 135–142.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  61. Marini A. M. and Nowak T. S., Jr. (2000) Metabolic effects of 1-methyl-4-phenylpyridinium (MPP(+)) in primary neuron cultures. J. Neurosci. Res. 62, 814–820.

    Article  PubMed  CAS  Google Scholar 

  62. Gonzalez-Polo R. A., Soler G., Alonso J. C., Rodriguez-Martin A., and Fuentes J. M. (2003) MPP(+) causes inhibition of cellular energy supply in cerebellar granule cells. Neurotoxicology 24, 219–225.

    Article  PubMed  CAS  Google Scholar 

  63. Bates T. E., Heales S. J., Davies S. E., Boakye P., and Clark J. B. (1994) Effects of 1-methyl-4-phenylpyridinium on isolated rat brain mitochondria: evidence for a primary involvement of energy depletion. J. Neurochem. 63, 640–648.

    Article  PubMed  CAS  Google Scholar 

  64. Chalmers-Redman R. M., Fraser A. D., Carlile G. W., Pong A., and Tatton W. G. (1999) Glucose protection from MPP+-induced apoptosis depends on mitochondrial membrane potential and ATP synthase. Biochem. Biophys. Res. Commun. 257, 440–447.

    Article  PubMed  CAS  Google Scholar 

  65. Storch A., Kaftan A., Burkhardt K., and Schwarz J. (2000) 1-Methy1-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy metabolism. Brain Res. 855, 67–75.

    Article  PubMed  CAS  Google Scholar 

  66. Desagher S. and Martinou J. C. (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol. 10, 369–377.

    Article  PubMed  CAS  Google Scholar 

  67. Vila M., Jackson-Lewis V., Vukosavic S., et al. (2001) Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 98, 2837–2842.

    Article  PubMed  CAS  Google Scholar 

  68. Putcha G. V., Deshmukh M., and Johnson E. M., Jr. (1999) BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J. Neurosci. 19, 7476–7485.

    PubMed  CAS  Google Scholar 

  69. Jungas T., Motta I., Duffieux F., Fanen P., Stoven V., and Ojcius D. M. (2002) Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 277, 27,912–27,918.

    Article  CAS  Google Scholar 

  70. Antonsson B., Montessuit S., Lauper S., Eskes R., and Martinou J. C. (2000) Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem. J. 345 (Pt 2), 271–278.

    Article  PubMed  CAS  Google Scholar 

  71. Zha J., Harada H., Yang E., Jockel J., and Korsmeyer S. J. (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87, 619–628.

    Article  PubMed  CAS  Google Scholar 

  72. Dudek H., Datta S. R., Franke T. F., et al. (1997) Regulation of neuronal survival by the serinethreonine protein kinase Akt. Science 275, 661–665.

    Article  PubMed  CAS  Google Scholar 

  73. Desagher S., Osen-Sand A., Nichols A., et al. (1999) Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J. Cell Biol. 144, 891–901.

    Article  PubMed  CAS  Google Scholar 

  74. Kudla G., Montessuit S., Eskes R., et al. (2000) The destabilization of lipid membranes induced by the C-terminal fragment of caspase 8-cleaved bid is inhibited by the N-terminal fragment. J. Biol. Chem. 275, 22,713–22,718.

    Article  CAS  Google Scholar 

  75. Mosmann T. (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65, 55–63.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Veterinaria, Universidad de Extremadura, Cáceres, Spain

    Germán Soler

  2. Departamento de Bioquímica y Biología Molecular y Genética, E.U. Enfermería y T.O., Universidad de Extremadura, Cáceres, Spain

    Rosa A. González-Polo & José M. Fuentes

Authors
  1. Rosa A. González-Polo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Germán Soler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José M. Fuentes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José M. Fuentes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

González-Polo, R.A., Soler, G. & Fuentes, J.M. MPP+ . Mol Neurobiol 30, 253–264 (2004). https://doi.org/10.1385/MN:30:3:253

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:30:3:253

Index Entries

Search

Navigation