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Ginkgo biloba Extracts EGb 761 and Bilobalide Increase NADH Dehydrogenase mRNA Level and Mitochondrial Respiratory Control Ratio in PC12 Cells

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Abstract

In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a ∼2-fold significant increase in ND1 mRNA level, after 48 and 72 h exposure to 100 μg/ml EGb 761 and to 10 μg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

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REFERENCES

  1. Gutteridge, J. M. and Halliwell, B. 2000. Free radicals and antioxidants in the year 2000. A historical look to the future. Ann N Y Acad. Sci. 899:136–147.

    Google Scholar 

  2. Turrens, J. F. and Boveris, A. 1980. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem. J. 191:421–427.

    Google Scholar 

  3. Singer, T. P., Ramsay, R. R., and Ackrell, B. A. 1995. Deficiency of NADH and succinate dehydrogenase in degenerative diseases and myophathies. Biochim. Biophys. Acta. 1271:211–219.

    Google Scholar 

  4. Villa, R. F., Turpeenoja, L., Magri, G., Gorini, A., Ragusa, N., and Giuffrida-Stella, A. M. 1991. Effect of hypoxia on mitochondrial protein composition of cerebral cortex during aging. Neurochem. Res. 16:821–826.

    Google Scholar 

  5. Bowling, A. C., Mutisya, E. M., Walker, L. C., Price, D. L., Cork, L. C., and Beal, M. F. 1993. Age-dependent impairment of mitochondrial function in primate brain. J. Neurochem. 60:1964–1967.

    Google Scholar 

  6. Shigenaga, M. K., Hagen, T. M., and Ames, B. N. 1994. Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA 91:10771–10778.

    Google Scholar 

  7. Nicoletti, V. G., Tendi, E. A., Lalicata, C., Reale, S., Costa, A., Villa, R. F., Ragusa, N., and Giuffrida Stella, A. M. 1995. Changes of mitochondrial cytochrome c oxidase and F0F1 ATP synthase subunits in rat cerebral cortex during aging. Neurochem. Res. 20:1465–1470.

    Google Scholar 

  8. Jenner, P., Schapira, A. H., and Marsden, C. D. 1992. New insights into the cause of Parkinson's disease. Neurology 42:2241–2250.

    Google Scholar 

  9. Behl, C., Davis, J. B., Lesley, R., and Schubert, D. 1994. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817–827.

    Google Scholar 

  10. Arenas, J., Campos, Y., Ribacoba, R., Martin, M. A., Rubio, J. C., Ablanedo, P., and Cabello, A. 1998. Complex I defect in muscle from patients with Huntington's disease. Ann. Neurol. 43:397–400.

    Google Scholar 

  11. Calabrese, V., Bates, T. E., and Stella, A. M. 2000. NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance. Neurochem. Res. 25:1315–1341.

    Google Scholar 

  12. Drieu, K. 1986. Preparation and definition of Ginkgo biloba extract. Presse Med. 15:1455–1457.

    Google Scholar 

  13. DeFeudis, F. V. 1998. Ginkgo biloba extract (EGb 761): from chemistry to the clinic. Ullstein Medical.

  14. Hoyer, S., Lannert, H., Noldner, M., and Chatterjee, S. S. 1999. Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761). J. Neural. Transm. 106:1171–1188.

    Google Scholar 

  15. Kanowski, S., Herrmann, W. M., Stephan, K., Wierich, W., and Horr, R. 1996. Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multiinfarct dementia. Pharmacopsychiatry 29:47–56.

    Google Scholar 

  16. Janssens, D., Michiels, C., Delaive, E., Eliaers, F., Drieu, K., and Remacle, J. 1995. Protection of hypoxia-induced ATP decrease in endothelial cells by ginkgo biloba extract and bilobalide. Biochem. Pharmacol. 50:991–999.

    Google Scholar 

  17. Janssens, D., Remacle, J., Drieu, K., and Michiels, C. 1999. Protection of mitochondrial respiration activity by bilobalide. Biochem. Pharmacol. 58:109–119.

    Google Scholar 

  18. Bosetti, F., Solaini, G., Tendi, E. A., Chikhale, E. G., Chandrasekaran, K., and Rapoport, S. I. 2001. Mitochondrial cytochrome c oxidase subunit III is selectively down-regulated by aluminum exposure in PC12S cells. Neuroreport. 12:721–724.

    Google Scholar 

  19. Gadaleta, G., Pepe, G., De Candia, G., Quagliariello, C., Sbisa, E., and Saccone, C. 1989. The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome: cryptic signals revealed by comparative analysis between vertebrates. J. Mol. Evol. 28:497–516.

    Google Scholar 

  20. Nicoletti, V. G., Tendi, E. A., Console, A., Privitera, A., Villa, R. F., Ragusa, N., and Giuffrida-Stella, A. M. 1998. Regulation of cytochrome c oxidase and F0F1-ATPase subunits expression in rat brain during aging. Neurochem. Res. 23:55–61.

    Google Scholar 

  21. Bai, Y., Shakeley, R. M., and Attardi, G. 2000. Tight control of respiration by NADH dehydrogenase ND5 subunit gene expression in mouse mitochondria. Mol. Cell. Biol. 20:805–815.

    Google Scholar 

  22. Lenaz, G., D'Aurelio, M., Merlo Pich, M., Genova, M. L., Ventura, B., Bovina, C., Formiggini, G., and Parenti Castelli, G. 2000. Mitochondrial bioenergetics in aging. Biochim. Biophys. Acta. 1459:397–404.

    Google Scholar 

  23. Davey, G. P., Peuchen, S., and Clark, J. B. 1998. Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration. J. Biol. Chem. 273:12753–12757.

    Google Scholar 

  24. Chandrasekaran, K., Liu, L. I., Hatanpaa, K., Drieu, K., and Rapoport, S. I. 1998. Stimulation of mitochondrial gene expression by bilobalide, a component of Ginkgo biloba extract (EGb 761). Advances in Ginkgo biloba Extract Research, Vol. 7. Pages 121–128, Packer, L., and Chisten, Y. (eds.) Elsevier, Paris.

    Google Scholar 

  25. Watanabe, C. M., Wolffram, S., Ader, P., Rimbach, G., Packer, L., Maguire, J. J., Schultz, P. G., and Gohil, K. 2001. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc. Natl. Acad. Sci. USA 98:6577–6580.

    Google Scholar 

  26. Mizuno, M., Droy-Lefaix, M. T., and Packer, L. 1996. Gingko biloba extract EGb 761 is a suppresser of AP-1 transcription factor stimulated by phorbol 12–myristate 13–acetate. Biochem. Molec. Biol. Int. 39:395–401.

    Google Scholar 

  27. Schapira, A. H. 1999. Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia. Biochim. Biophys. Acta. 1410:159–170.

    Google Scholar 

  28. Jha, N., Jurma, O., Lalli, G., Liu, Y., Pettus, E. H., Greenamyre, J. T., Liu, R. M., Forman, H. J., and Andersen, J. K. 2000. Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. J. Biol. Chem. 275:26096–26101.

    Google Scholar 

  29. Paradies, G., Petrosillo, G., Pistolese, M., Di Venosa, N., Serena, D., and Ruggiero, F. M. 1999. Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radic. Biol. Med. 27:42–50.

    Google Scholar 

  30. Borutaite, V., Mildaziene, V., Brown, G. C., and Brand, M. D. 1995. Control and kinetic analysis of ischemia-damaged heart mitochondria: which parts of the oxidative phosphorylation system are affected by ischemia? Biochim. Biophys. Acta. 1272:154–158.

    Google Scholar 

  31. Janssens, D., Remacle, J., Drieu, K., and Michiels, C. 1999. Protection of mitochondrial respiration activity by bilobalide. Biochem. Pharmacol. 58:109–119.

    Google Scholar 

  32. Janssens, D., Delaive, E., Remacle, J., and Michiels, C. 2000. Protection by bilobalide of the ischaemia-induced alterations of the mitochondrial respiratory activity. Fundam. Clin. Pharmacol. 3:193–201.

    Google Scholar 

  33. Marcus, D. L., Thomas, C., Rodriguez, C., Simberkoff, K., Tsai, J. S., Strafaci, J. A., and Freedman, M. L. 1998. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. Exp. Neurol. 150:40–44.

    Google Scholar 

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Tendi, E.A., Bosetti, F., DasGupta, S.F. et al. Ginkgo biloba Extracts EGb 761 and Bilobalide Increase NADH Dehydrogenase mRNA Level and Mitochondrial Respiratory Control Ratio in PC12 Cells. Neurochem Res 27, 319–323 (2002). https://doi.org/10.1023/A:1014963313559

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  • DOI: https://doi.org/10.1023/A:1014963313559

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