Abstract
The effect of glutathione depletion, in vivo, on rat brain nitric oxide synthase activity has been investigated and compared to the effect observed in vitro with cultured neurones. Using L-buthionine sulfoximine rat brain glutathione was depleted by 62%. This loss of glutathione was accompanied by a significant increase in brain nitric oxide synthase activity by up to 55%. Depletion of glutathione in cultured neurones, by approximately 90%, led to a significant 67% increase in nitric oxide synthase activity, as judged by nitrite formation, and cell death. It is concluded that depletion of neuronal glutathione results in increased nitric oxide synthase activity. These findings may have implications for our understanding of the pathogenesis of neurodegenerative disorders in which loss of brain glutathione is considered to be an early event.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bredt, D. S. and Snyder, S. H. 1989. Nitric oxide mediates glutamate linked enhancement of cGMP levels in the cerebellum. Proc. Natl. Acad. Sci. USA, 86:9030–9033.
Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S. and Snyder, S. H. 1991. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA, 88:6368–6371.
Johnson, A. W., Land, J. M., Thompson, E. J., Bolaños, J. P., Clark, J. B., and Heales, S. J. R. 1995. Evidence for increased nitric oxide production in multiple sclerosis. J. Neurol. Neurosurg. Psych., 58:107.
Bolaños, J. P., Peuchen, S. P., Heales, S. J. R., Land, J. M., and Clark, J. B. 1994. Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J. Neurochem., 63:910–916.
Bolaños, J. P., Heales, S. J. R., Land, J. M., and Clark, J. B. 1995. Effect of peroxynitrite on the mitochondrial respiratory chain: Differential suceptibility of neurones and astrocytes in primary culture. J. Neurochem., 64:1965–1972.
Knowles, R. G., and Moncada, S. 1994. Nitric oxide synthases in mammals. Biochem. J., 298:249–258.
Stuehr, D. J., Kwon, N. S., and Nathan, C. F. 1990. FAD and GSH participate in macrophage synthesis of nitric oxide. Biochem. Biophys. Res. Commun., 168:558–565.
Giovenelli, J., Campos, K. L., and Kaufman, S. 1991. Tetraydrobiopterin, a cofactor for rat cerebellar nitric oxide synthase, does not function as a reactant in the oxygenation of arginine. Proc. Natl. Acad. Sci. USA, 88:7091–7095.
DiMonte, D. A., Chan, P., and Sandy, M. S. 1992. Glutathione in Parkinson’s Disease: A link between oxidative stress and mitochondrial damage? Ann. Neurol. 32:S111–115.
Meister, A. and Larsson, A. (1989) Glutathione synthetase deficiency and other disorders of the γ-glutamyl cycle. Pages 855–868.In C. R. Scriver C. R., Beaudet A. L., Sly W. S., and Valle D. (Eds). The Metabolic Basis of Inherited Disease, McGraw-Hill, New York.
Cho, E. I., Sahyoun, N. and Stegink, L. D. 1981. Tissue glutathione as a cyst(e)ine reservoir during fasting and refeeding of rats. J. Nutr., 111:914–922.
Squadrito, F., Calapai, G., Altavilla, D., Cucinotta, D., Zingarelli, B., Campo, G. M., Arcoraci, V., Sautebin, L., Mazzaglia, G., and Caputi, A. P. 1994. Food deprivation increases brain nitric oxide synthase and depresses brain serotonin levels in rats. Neuropharmacol., 33:83–86.
Jain, A., Martensson, J., Stole, E., Auld, P. A. M., and Meister, A. 1991. Glutathione deficiency leads to mitochondrial damage in brain. Proc. Natl. Acad. Sci. USA., 88:1913–1917.
Heales, S. J. R., Davies, S. E. C., Bates, T. E. and Clark, J. B. 1995. Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration. Neurochem. Res., 20:31–38.
Tabermero, A., Bolaños, J. P., and Medina, J. M. 1993. Lipogenesis from lactate in rat neurones and astrocytes in primary culture Biochem. J., 294:635–638.
Riederer, P., Sofic, E., Rausch, W.-D., Schmidt, B., Reynolds, G. P., Jellinger, K., and Youdim M. B. H. 1989. Transition metals, ferritin, glutathione and ascorbic acid in Parkinsonian brains. J. Neurochem., 52:512–520.
Hyland, K., Smith, I., Howells, D. W., Clayton, P. T. and Leonard, J. V. 1985. The determination of pterins, biogenic amine metabolites and aromatic amino acids in cerebrospinal fluid using isocratic reverse phase liquid chromatography with in series dual cell coulometric electrochemical detection and florescence detection: Use in the study of inborn errors of dihydropteridine reductase and 5, 10 methylenetetrahydrofolate reductase. Pages 85–99.in H. Wachter, H. Ch. Curtius and W. Pfleiderer (eds), Biochemical and Clinical Aspects of Pteridines, Vol. 4, De Gruyter, Berlin.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and randall, R. J. 1951. Protein measurement with Folin phenol reagent. J. Biol. Chem., 193:265–275.
Griscavage, J. M., Fukuto, J. M., Komori, Y. and Ignarro, L. J. 1994. Nitric oxide inhibits neuronal nitric oxide by interacting with the heme prosthetic group. J. Biol. Chem., 269:21644–21649.
Hevel, J. M. and Marletta, M. A. 1994. Nitric oxide synthase assays. Methods in Enzymology., 233:250–258.
Klatt, P., Schmid, M., Leopold, E., Schmidt, K., Werner, E. R. and Mayer, B. 1994. The pteridine binding site of brain nitric oxide synthase. J. Biol. Chem., 269:13861–13866.
Ratan, R. R., Murphy, T. H., and Baraban, J. M. 1994. Macromolecular synthesis inhibitors prevent oxidative stress induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione. J. Neurosci., 14:4385–4392.
Herdegen, T., Brecht, S., Mayer, B., Leah, J., Kummer, W., Bravo, R. and Zimmerman, M. 1993. Long lasting expression of jun and krox transcription factors and nitric oxide synthase in intrinsic neurones of the rat brain following axotomy. J. Neurosci., 13:4130–4145.
Verge, V. M. K., Xu, Z., Xu, X. J., Wiesenfeldhallin, Z. and Hokfelt, T. 1992. Marked increase in nitric oxide synthase messenger RNA in rat dorsal root ganglia after peripheral axotomyin situ hybridisation and functional studies. Proc. Natl. Acad. Sci. USA., 89:11616–11621.
Jenner, P., Dexter, D. T., Sian, J., Schapira, A. H. V., and Marsden C. D. 1992. Oxidative stress as a cause of nigral cell death in Parkinson’s Disease and incidental Lewy body disease. Ann. Neurol. 32:S82–87.
Schapira, A. H. V., Cooper, J. M., Dexter, D., Clark, J. B., Jenner, P., and Marsden, C. D. 1990. Mitochondrial complex I deficiency in Parkinson’s Disease. J. Neurochem., 54:823–827.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Heales, S.J.R., Bolaños, J.P. & Clark, J.B. Glutathione depletion is accompanied by increased neuronal nitric oxide synthase activity. Neurochem Res 21, 35–39 (1996). https://doi.org/10.1007/BF02527669
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02527669