Metabolic Brain Disease

, Volume 18, Issue 2, pp 147–154 | Cite as

In Vitro Effect of Homocysteine on Some Parameters of Oxidative Stress in Rat Hippocampus

  • Emilio L. Streck
  • Paula S. Vieira
  • Clóvis M. D. Wannmacher
  • Carlos S. Dutra-Filho
  • Moacir Wajner
  • Angela T. S. Wyse
Article

Abstract

Homocystinuria is an inherited metabolic disease characterized biochemically by increased blood and brain levels of homocysteine caused by severe deficiency of cystathionine β-synthase activity. Affected patients present mental retardation, seizures, and atherosclerosis. Oxidative stress plays an important role in the pathogenesis of many neurodegenerative and vascular diseases, such Alzheimer's disease, stroke, and atherosclerosis. However, the mechanisms underlying the neurological damage characteristic of homocystinuria are still poorly understood. To evaluate the involvement of oxidative stress on the neurological dysfunction present in homocystinuria, we measured thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and total radical-trapping antioxidant potential (TRAP) and antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase) in rat hippocampus in the absence (controls) or in the presence of homocysteine (10–500 μM) in vitro. We demonstrated that homocysteine significantly increases TBARS and decreases TRAP, both in a dose-dependent manner, but did not change antioxidant enzymes. Our results suggest that oxidative stress is involved in the neurological dysfunction of homocystinuria. However, further studies are necessary to confirm and extend our findings to the human condition and also to determine whether antioxidant therapy may be of benefit to these patients.

Homocysteine homocystinuria oxidative stress TBARS TRAP antioxidant enzymes 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aebi, H. (1984). Catalase in vitro. Methods Enzymol. 105:121-126.Google Scholar
  2. Cavalca, V., Cighetti, G., Bamonti, F., Loaldi, A., Bortone, L., Novembrino, C., De Franceschi, M., Belardinelli, R., and Guazzi, M.D. (2001). Oxidative stress and homocysteine in coronary artery disease. Clin. Chem. 47:887-892.Google Scholar
  3. De Franchis, R., Sperandeo, M.P., Sebastio, G., and Andria, G. (1998). Clinical aspects of cystathionine β-synthase: How wide is the spectrum? Eur. J. Pediatr. 157(Suppl. 2):S67-S70.Google Scholar
  4. Esterbauer, H., and Cheeseman, K.H. (1990). Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hydroxynonenal. Methods Enzymol. 186:407-421.Google Scholar
  5. Fowler, B. (1997). Disorders of homocysteine metabolism. J. Inher. Metab. Dis. 20:270-285.Google Scholar
  6. Halliwell, B. (1996). Free radicals, proteins and DNA: Oxidative damage versus redox regulation. Biochem. Soc. Trans. 24:1023-1027.Google Scholar
  7. Halliwell, B., and Gutteridge, J.M.C. (1985). Oxygen radicals and nervous system. Trends Neurosci. 8:22-26.Google Scholar
  8. Ho, P.I., Ortiz, D., Rogers, E., and Shea, T.B. (2002). Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage. J. Neurosci. Res. 70:694-702.Google Scholar
  9. Hogg, N. (1999). The effect of cyst(e)ine on the auto-oxidation of homocysteine. Free Rad. Biol. Med. 27:28-33.Google Scholar
  10. Kim, W.K., and Pae, Y.S. (1996). Involvement of N-methyl-D-aspartate receptor and free radical in homocysteine-mediated toxicity on rat cerebellar granule cells in culture. Neurosci. Lett. 216:117-120.Google Scholar
  11. Kraus, J.P. (1998). Biochemistry and molecular genetics of cystathionine β-synthase deficiency. Eur. J. Pediatr. 157(Suppl. 2):S50-S53.Google Scholar
  12. Kuhn, W., Roebroek, R., Blom, H., van Oppenraaij, D., Przuntek, H., Kretschmer, A., Buttner, T., Woitalla, D., and Muller, T. (1998). Elevated plasma levels of homocysteine in Parkinson's disease. Eur. Neurol. 40:225-227.Google Scholar
  13. Leblhuber, F., Walli, J., Artner-Dworzak, E., Vrecko, K., Widner, B., Reibnegger, G., and Fuchs, D. (2000). Hyperhomocysteinemia in dementia. J. Neural Transm. 107:343-353.Google Scholar
  14. Lees, G.J. (1993). Contributory mechanisms in the causation of neurodegenerative disorders. Neuroscience 54:287-322.Google Scholar
  15. Lipton, S.A., Kim, W.K., Choi, Y.B., Kumar, S., D'Emilia, D.M., Rayudu, P.V., Arnelle, D.R., and Stamler, J.S. (1997). Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. U.S.A. 94: 5923-5928.Google Scholar
  16. Lissi, E., Pascual, C., and Del Castillo, M.D. (1992). Luminol luminescence induced by 2,2′-azo-bis(2-amidinopropane) thermolysis. Free Radic. Res. Commun. 17:299-311.Google Scholar
  17. Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265-275.Google Scholar
  18. Malinow, M.R. (1990). Hyperhomocyst(e)inemia. A common and easily reversible risk factor for occlusive atherosclerosis. Circulation 81:2004-2006.Google Scholar
  19. Mudd, S.H., Levy, H.L., and Skovby, F. (2001). Disorders of transulfuration. In (C.R. Scriver, A.L. Beaudet, W.S. Sly, and D. Valle, eds.), The Metabolic and Molecular Bases of Inherited Disease. 8th edn., McGraw-Hill, New York, pp. 1279-1327.Google Scholar
  20. Parnetti, L., Bottiglieri, T., and Lowenthal, D. (1997). Role of homocysteine in age-related vascular and non-vascular diseases. Aging (Milano) 9:241-257.Google Scholar
  21. Reznick, A.Z., and Packer, L. (1993). In (G. Poli, E. Albano, and M.U. Dianzani, eds.), Free radicals: From Basic Science to Medicine, Birkhäuser, Basel, pp. 425-437.Google Scholar
  22. Schurr, A. (2002). Energy metabolism, stress hormones and neural recovery from cerebral ischemia/hypoxia. Neurochem. Int. 41:1-8.Google Scholar
  23. Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D'Agostino, R.B., Wilson, P.W.F., and Wolf, P.A. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 346:476-483.Google Scholar
  24. Streck, E.L., Zugno, A.I., Tagliari, B., Franzon, R., Wannmacher, C.M.D., Wajner, M., and Wyse, A.T.S. (2001). Inhibition of rat brain Na+,K+-ATPase activity induced by homocysteine is probably mediated by oxidative stress. Neurochem. Res. 26:1195-1200.Google Scholar
  25. Temple, M.E., Luzier, A.B., and Kaazierad, D.J. (2000). Homocysteine as a risk factor for atherosclerosis. Ann. Pharmacother. 34:57-65.Google Scholar
  26. Ueland, P.M., and Refsum, H. (1989). Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease, and drug therapy. J. Lab. Clin. Med. 114:473-501.Google Scholar
  27. Welch, G.N., Upchurch, G.R., and Loscalzo, J. (1997). Homocysteine, oxidative stress, and vascular disease. Hosp. Pract. 32:81-92.Google Scholar
  28. Wendel, A. (1981). Glutathione peroxidase. Methods Enzymol. 77:325-332.Google Scholar
  29. White, A.R., Huang, X., Jobling, M.F., Barrow, C.J., Beyreuther, K., Masters, C.L., Bush, A.I., and Cappai, R. (2001). Homocysteine potentiates copper-and amyloid beta peptide-mediated toxicity in primary neuronal cultures: Possible risk factors in the Alzheimer's-type neurodegenerative pathways. J. Neurochem. 76:1509-1520.Google Scholar
  30. Wyse, A.T.S., Zugno, A.I., Streck, E.L., Matté, C., Calcagnotto, T., Wannmacher, C.M.D., and Wajner, M. (2002). Inhibition of Na+,K+-ATPase activity in hippocampus of rats subjected to acute administration of homocysteine is prevented by vitamins E and C treatment. Neurochem. Res. 27:1677-1681.Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Emilio L. Streck
    • 1
  • Paula S. Vieira
    • 1
  • Clóvis M. D. Wannmacher
    • 1
  • Carlos S. Dutra-Filho
    • 1
  • Moacir Wajner
    • 1
  • Angela T. S. Wyse
    • 1
  1. 1.Departamento de Bioquímica, ICBSUniversidade Federal do Rio Grande do SulPorto Alegre, RSBrazil

Personalised recommendations