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A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds

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Abstract

CONGENERS of nitrogen monoxide (NO) are neuroprotective and neurodestructive1– 7. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+)8. Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity3,4. Here, we report that NO.-mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O.-2), apparently leading to formation of peroxynitrite (ONOO−), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site1. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.

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References

  1. Lei, S. Z. et al. Neuron 8, 1087–1099 (1992).

    Article  CAS  Google Scholar 

  2. Manchester, K. S., Jensen, F. E., Warach, S. &. Lipton, S. A. Neurology 43, A365 (1993).

    Google Scholar 

  3. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S. & Snyder, S. H. Proc. natn. Acad. Sci. U.S.A. 88, 6368–6371 (1991).

    Article  ADS  CAS  Google Scholar 

  4. Dawson, T. M., Dawson, V. L. & Snyder, S. H. Ann. Neurol. 32, 297–311 (1992).

    Article  CAS  Google Scholar 

  5. Nowicki, J. P., Duval, D., Poignet, H. & Scatton, B. Eur. J. Pharmac. 204, 339–340 (1991).

    Article  CAS  Google Scholar 

  6. Moncada, C., Lekieffre, D., Arvin, B. & Meldrum, B. Neuroreport 3, 530–532 (1992).

    Article  CAS  Google Scholar 

  7. Wallis, R. A., Panizzon, K. & Wasterlain, C. G. Neuroreport 3, 645–648 (1992).

    Article  CAS  Google Scholar 

  8. Stamier, J. S., Singel, D. J. & Loscalzo, J. Science 258, 1898–1902 (1992).

    Article  ADS  Google Scholar 

  9. Hogg, N., Darley-Usmar, V. M., Wilson, M. T. & Moncada, S. Biochem. J. 281, 419–424 (19923.

  10. Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A. & Freeman, B. A. Proc. natn. Acad. Sci. U.S.A. 87, 1620–1624 (1990).

    Article  ADS  CAS  Google Scholar 

  11. Radi, R., Beckman, J. S., Bush, K. M. & Freeman, B. A. J. biol. Chem. 266, 4244–4250 (1991).

    CAS  PubMed  Google Scholar 

  12. Radi, R., Beckman, J. S., Bush, K. M. & Freeman, B. A. Arch. Biochem. Biophys. 288, 481–487 (1991).

    Article  CAS  Google Scholar 

  13. Koppenol, W. H., Moreno, J. J., Pryor, W. A., Ischiropoulos, H. & Beckman, J. S. Chem. Res. Toxicol. 5, 834–842 (1992).

    Article  CAS  Google Scholar 

  14. Feelisch, M., Ostrowski, J. & Noack, E. J. cardiovasc. Pharmac. 14 (suppl. 11), S13–S22 (1989).

    Article  CAS  Google Scholar 

  15. Ignarro, L. J. Hypertension 16, 477–483 (1990).

    Article  CAS  Google Scholar 

  16. Ischiropoulos, H. et al. Arch. Biochem. Biophys. 298, 431–437 (1992).

    Article  CAS  Google Scholar 

  17. Oury, T. D., Ho, Y.-S. Piantadosi, C. A. & Crapo, J. D. Proc. natn. Acad. Sci. U.S.A. 89, 9715–9719 (1992).

    Article  ADS  CAS  Google Scholar 

  18. Bates, J. N., Baker, M. T., Guerra, R. Jr & Harrison, D. G. Biochem. Pharmac. 42 (suppl.), S157–S165 (1991).

    Article  CAS  Google Scholar 

  19. Marks, G. S., McLaughlin, B. E., Nakatsu, K. & Brien, J. F. Can. J. Physiol. Pharmac. 70, 308–311 (1992).

    Article  CAS  Google Scholar 

  20. Ignarro, L. J. et al. J. Pharmac. exp. Ther. 218, 739–749 (1981).

    CAS  Google Scholar 

  21. Noack, E. & Feelisch, M. Basic Res. Cardiol. 86 (suppl. 2), 37–50 (1991).

    PubMed  Google Scholar 

  22. Olney, J. W., Zorumski, C., Price, M. T. & Labryuere, J. Science 248, 596–599 (1990).

    Article  ADS  CAS  Google Scholar 

  23. Zumft, W. G. & Frunzke, K. Biochim. biophys. Acta 681, 459–468 (1982).

    Article  CAS  Google Scholar 

  24. Hoyt, K. R., Tang, L.-H., Aizenman, E. & Reynolds, I. J. Brain Res. 592, 310–316 (1992).

    Article  CAS  Google Scholar 

  25. Pryor, W. A., Church, D. F., Govinden, C. K. & Crank, G. J. org. Chem. 47, 156–159 (1982).

    Article  CAS  Google Scholar 

  26. Feelisch, M. J. cardiovasc. Pharmac. 17 (suppl. 3), S25–S33 (1991).

    Article  CAS  Google Scholar 

  27. Sucher, N. J. & Lipton, S. A. J. Neurosci. Res. 30, 582–591 (1991).

    Article  CAS  Google Scholar 

  28. Choi, D. W. Neuron 1, 623–634 (1988).

    Article  CAS  Google Scholar 

  29. Meldrum, B. & Garthwaite, J. Trends pharmacol. Sci. 11, 379–387 (1990).

    Article  CAS  Google Scholar 

  30. Lipton, S. A. Trends Neurosci. 15, 75–79 (1992).

    Article  CAS  Google Scholar 

  31. Bredt, D. S., Hwang, P. M. & Snyder, S. H. Nature 347, 768–770 (1990).

    Article  ADS  CAS  Google Scholar 

  32. Liu, T. H., Beckman, J. S. Freeman, B. A., Hogan, E. L. & Hsu, C. Y. Am. J. Physiol. 256, 589–593 (1989).

    Google Scholar 

  33. Kinouchi, H. et al. Proc. natn. Acad. Sci. U.S.A. 89, 11158–11162 (1991).

    Article  ADS  Google Scholar 

  34. Stamler, J. S. et al. Proc. natn. Acad. Sci. U.S.A. 89, 444–448 (1991).

    Article  ADS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Cellular * Molecular Neuroscience, Children's Hospital,

    Stuart A. Lipton, Yun-Beom Choi, Zhuo-Hua Pan, Sizheng Z. Lei, Huei-Sheng Vincent Chen & Nikolaus J. Sucher

  2. Program in Neuroscience, Harvard Medical School, 300 Longwood Avenue, Enders Building, Suite 361, Boston, Massachusetts, 02115, USA

    Stuart A. Lipton, Yun-Beom Choi, Zhuo-Hua Pan, Sizheng Z. Lei, Huei-Sheng Vincent Chen & Nikolaus J. Sucher

  3. Departments of Neurology Children's Hospital, Beth Israel Hospital, Massachusetts General Hospital, Boston, Massachusetts, 02115, USA

    Stuart A. Lipton

  4. Neurology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Stuart A. Lipton

  5. Cardiovascular, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Joseph Loscalzo

  6. Respiratory Divisions, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Jonathan S. Stamler

  7. Cardiology Section, Brockton/West Roxbury Veterans Administration Medical Center, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Joseph Loscalzo & Jonathan S. Stamler

  8. Department of Chemistry, Harvard University, Cambridge, Massachusetts, 02138, USA

    David J. Singel

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  1. Stuart A. Lipton
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  9. Jonathan S. Stamler
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Lipton, S., Choi, YB., Pan, ZH. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993). https://doi.org/10.1038/364626a0

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  • DOI: https://doi.org/10.1038/364626a0

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