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Antioxidant Effect of Phenelzine on MPP+-Induced Cell Viability Loss in Differentiated PC12 Cells

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Abstract

Phenelzine, deprenyl, and antioxidants (SOD, catalase, ascorbate, or rutin) reduced the loss of cell viability in differentiated PC12 cells treated with 250 μM MPP+, whereas N-acetylcysteine and dithiothreitol did not inhibit cell death. Phenelzine reduced the condensation and fragmentation of nuclei caused by MPP+ in PC12 cells. Phenelzine and deprenyl prevented the MPP+-induced decrease in mitochondrial membrane potential, cytochrome c release, formation of reactive oxygen species, and depletion of GSH in PC12 cells. Phenelzine revealed a scavenging action on hydrogen peroxide and reduced the hydrogen peroxide–induced cell death in PC12 cells, whereas deprenyl did not depress the cytotoxic effect of hydrogen peroxide. Both compounds reduced the iron and EDTA-mediated degradation of 2-deoxy-d-ribose degradation. The results suggest that phenelzine attenuates the MPP+-induced viability loss in PC12 cells by reducing the alteration of mitochondrial membrane permeability that seems to be mediated by oxidative stress.

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REFERENCES

  1. Bernardi, P. 1996. The permeability transition pore: Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. Biochim. Biophys. Acta 1275:5-9.

    Google Scholar 

  2. Lotharius, J., Dugan, L. L., and O'Malley, K. L. 1999. Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. J. Neurosci. 19:1284-1293.

    Google Scholar 

  3. Atlante, A., Calissano, P., Bobba, A., Giannattasio, S., Marra, E., and Passarella, S. 2001. Glutamate neurotoxicity, oxidative stress and mitochondria. FEBS Lett. 497:1-5.

    Google Scholar 

  4. Cassarino, D. S., Parks, J. K., Parker, W. D. Jr., and Bennett, J. P. Jr., 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 1453:49-62.

    Google Scholar 

  5. Chakraborati, T., Das, S., Mondal, M., Roychoudhury, S., and Chakraborti, S. 1999. Oxidant, mitochondria and calcium: An overview. Cell. Signal. 11:77-85.

    Google Scholar 

  6. Chandra, J., Samali, A., and Orrenius, S. 2000. Triggering and modulation of apoptosis by oxidative stress. Free Radic. Biol. Med. 29:323-333.

    Google Scholar 

  7. Lee, C. S., Han, J. H., Jang, Y. Y., Song, J. H., and Han, E. S. 2002. Differential effect of catecholamines and MPP+ on membrane permeability in brain mitochondria and cell viability in PC12 cells. Neurochem. Int. 40:361-369.

    Google Scholar 

  8. Birkmayer, W., Knoll, J., Riederer, P., Youdim, M. B., Hars, V., and Marton, J. 1985. Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: A longterm study. J. Neural. Transm. 64:113-127.

    Google Scholar 

  9. Jacobsson, S. O. and Fowler, C. J. 1999. Dopamine and glutamate neurotoxicity in cultured chick telencephali cells: Effects of NMDA antagonists, antioxidants and MAO inhibitors. Neurochem. Int. 34:49-62.

    Google Scholar 

  10. Lai, C.-T. and Yu, P. H. 1997. Dopamine-and L-β-3,4-dihydroxyphenylalanine hydrochloride (L-DOPA)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells: Effects of oxidative stress and antioxidative factors. Biochem. Pharmacol. 53:363-372.

    Google Scholar 

  11. Maher, P. and Davis, J. B. 1996. The role of monoamine metabolism in oxidative glutamate toxicity. Neuroscience 16: 6394-6401.

    Google Scholar 

  12. Le, W., Jankovic, J., Xie, W., Kong, R., and Appel, S. H. 1997. (-)-Deprenyl protection of 1-methyl-4 phenylpyridium ion (MPP+)-induced apoptosis independent of MAO-B inhibition. Neurosci. Lett. 224:197-200.

    Google Scholar 

  13. Wu, R. M., Chen, R. C., and Chiueh, C. C. 2000. Effect of MAO-B inhibitors on MPP+ toxicity in vivo. Ann. NY Acad. Sci. 899:255-261.

    Google Scholar 

  14. Matsubara, K., Senda, T., Uezono, T., Awaya, T., Ogawa, S., Chiba, K., Shimizu, K., Hayase, N., and Kimura, K. 2001. L-Deprenyl prevents the cell hypoxia induced by dopaminergic neurotoxins, MPP(+) and beta-carbolinium: A microdialysis study in rats. Neurosci. Lett. 302:65-68.

    Google Scholar 

  15. Lee, C. S., Han, E. S., Jang, Y. Y., Han, J. H., Ha, H. W., and Kim, D. E. 2000. Protective effect of harmalol and harmaline on MPTP neurotoxicity in the mouse and dopamine-induced damage of brain mitochondria and PC12 Cells. J. Neurochem. 75: 521-531.

    Google Scholar 

  16. Kim, D. H., Jang, Y. Y., Han, E. S., and Lee, C. S. 2001. Protective effect of harmaline and harmalol against dopamine-and 6-hydroxydopamine-induced oxidative damage of brain mitochondria and synaptosomes, and viability loss of PC12 cells. Eur. J. Neurosci. 13:1861-1872.

    Google Scholar 

  17. Davis, J. M., Janicak, P. G., and Bruninga, K. 1987. The efficacy of MAO inhibitors in depression: A meta-analysis. Psychiatric Ann. 17:825-831.

    Google Scholar 

  18. Liebowitz, M. R. 1993. Depression with anxiety and atypical depression. J. Clin. Psychiatry 54(Suppl.):10-14.

    Google Scholar 

  19. Fredriksson, A., Palomo, T., and Archer, T. 2000. Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa. Behav. Pharmacol. 11: 571-581.

    Google Scholar 

  20. Tatton, W. G., Chalmers-Redman, R. M. E., Ju, W. J. H., Mammen, M., Carlile, G. W., Pong, A. W., and Tatton, N. A. 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: 753-764.

    Google Scholar 

  21. Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods 65:55-63.

    Google Scholar 

  22. Oberhammer, F. A., Pavelka, M., Sharma, S., Tiefenbacher, R., Purchio, A. F., Bursch, W., and Schulte-Hermann, R. 1992. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor β1. Proc. Natl. Acad. Sci. USA 89:5408-5412.

    Google Scholar 

  23. Fu, W., Luo, H., Parthasarathy, S., and Mattson, M. P. 1998. Catecholamines potentiate amyloid β-peptide neurotoxicity: Involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis. Neurobiol. Dis. 5:229-243.

    Google Scholar 

  24. van Klaveren, R. J., Hoet, P. H., Pype, J. L., Demedts, M., and Nemery, B. 1997. Increase in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes. Free Radic. Biol. Med. 22:525-534.

    Google Scholar 

  25. Aruoma, O. I. 1994. Deoxyribose assay for detecting hydroxyl radicals. Vol. 233, Pages 57-66, in Packer, L. (ed.), Methods enzymol. Academic Press, San Diego.

    Google Scholar 

  26. Du, Y., Dodel, R. C., Bales, K. R., Jemmerson, R., Hamiton-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.

    Google Scholar 

  27. Zeevalk, G. D., Bernard, L. P., Albers, D. S., Mirochnitchenko, O., Nicklas, W. J., and Sonsalla, P. K. 1997. Energy stress-induced dopamine loss in glutathione peroxidase-overexpressing transgenic mice and in glutathione-depleted mesencephalic cultures. J. Neurochem. 68:426-429.

    Google Scholar 

  28. Pereira, C. F. and Oliveira, C. R. 2000. Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis. Neurosci. Res. 37:227-236.

    Google Scholar 

  29. Halliwell, B. and Gutteridge, J. M. C. 1999. Detection of free radicals and other reactive species: Trapping and fingerprinting. Pages 351-429, in Halliwell, B. and Gutteridge, J. M. C. (eds.), Free radicals in biology and medicine. 3rd ed. Oxford University Press, New York.

    Google Scholar 

  30. Kadota, T., Yamaai, T., Saito, Y., Akita, Y., Kawashima, S., Moroi, K., Inagaki, N., and Kadota, K. 1996. Expression of dopamine transporter at the tips of growing neurites of PC12 cells. J. Histochem. Cytochem. 44:989-996.

    Google Scholar 

  31. Amarante-Mendes, G. P., Kim, C. N., Liu, L., Huang, Y., Perkins, C. L., Green, D. R., and Bhalla, K. 1998. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockade of mitochondrial release of cytochrome c and activation of caspase-3. Blood 91:1700-1705.

    Google Scholar 

  32. Tan, S., Sagara, Y., Liu, Y., Maher, P., and Schubert, D. 1998. The regulation of reactive oxygen species production during programmed cell death. J. Cell Biol. 141:1423-1432.

    Google Scholar 

  33. Jurma, O. P., Hom, D. G., and Andersen, J. K. 1997. Decreased glutathione results in calcium-mediated cell death in PC12. Free Radic. Biol. Med. 23:1055-1066.

    Google Scholar 

  34. Fonck, C. and Baudry, M. 2001. Toxic effects of MPP+ and MPTP in PC12 cells independent of reactive oxygen species formation. Brain Res. 905:199-206.

    Google Scholar 

  35. Obata, T., Yamanaka, Y., Kinemuchi, H., and Oreland, L. 2001. Release of dopamine by perfusion with 1-methyl-4-phenylpyridinium ion (MPP+) into the striatum is associated with hydroxyl free radical generation. Brain Res. 906:170-175.

    Google Scholar 

  36. Lotharius, J. and O'Malley, K. L. 2000. The Parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation: A novel mechanism of toxicity. J. Biol. Chem. 275: 38581-38588.

    Google Scholar 

  37. Obata, T. 2002. Dopamine efflux by MPTP and hydroxyl radical generation. J. Neural Transm. 109:1159-1180.

    Google Scholar 

  38. Tatton, W. G. and Chalmers-Redman, R. M. E. 1996. Modulation of gene expression rather than monoamine oxidase inhibition. Neurology 47(Suppl. 3):S171-S183.

    Google Scholar 

  39. Olanow, C. W. and Tatton, W. G. 1999. Etiology and pathogenesis of Parkinson's disease. Annu. Rev. Neurosci. 22:123-144.

    Google Scholar 

  40. Banaclocha, M. M., Hernandez, A. I., Martinez, N., and Ferrandiz, M. L. 1997. N-acetylcysteine protects against age-related increase in oxidized proteins in mouse synaptic mitochondria. Brain Res. 762:256-258.

    Google Scholar 

  41. Seaton, T. A., Cooper, J. M., and Schapira, A. H. 1997. Free radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors. Brain Res. 777:110-118.

    Google Scholar 

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Lee, C.S., Han, E.S. & Lee, W.B. Antioxidant Effect of Phenelzine on MPP+-Induced Cell Viability Loss in Differentiated PC12 Cells. Neurochem Res 28, 1833–1841 (2003). https://doi.org/10.1023/A:1026119708124

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  • DOI: https://doi.org/10.1023/A:1026119708124

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