Neurochemical Research

, Volume 31, Issue 9, pp 1141–1151

Chronic Lithium Treatment has Antioxidant Properties but does not Prevent Oxidative Damage Induced by Chronic Variate Stress

  • Ana Paula Santana de Vasconcellos
  • Fabiane Battistela Nieto
  • Leonardo Machado Crema
  • Luisa Amália Diehl
  • Lúcia Maria de Almeida
  • Martha Elisa Prediger
  • Elizabete Rocha da Rocha
  • Carla Dalmaz
Original Paper

Abstract

This study evaluated the effects of chronic stress and lithium treatments on oxidative stress parameters in hippocampus, hypothalamus, and frontal cortex. Adult male Wistar rats were divided into two groups: control and submitted to chronic variate stress, and subdivided into treated or not with LiCl. After 40 days, rats were killed, and lipoperoxidation, production free radicals, total antioxidant reactivity (TAR) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were evaluated. The results showed that stress increased lipoperoxidation and that lithium decreased free radicals production in hippocampus; both treatments increased TAR. In hypothalamus, lithium increased TAR and no effect was observed in the frontal cortex. Stress increased SOD activity in hippocampus; while lithium increased GPx in hippocampus and SOD in hypothalamus. We concluded that lithium presented antioxidant properties, but is not able to prevent oxidative damage induced by chronic variate stress.

Keywords

Lithium Chronic variate stress Oxidative stress SOD GPx Antioxidant enzymes Lipoperoxidation Free radicals 

References

  1. 1.
    McEwen BS (2000) Effects of adverse experiences for brain structure and function. Biol Psychiatry 48:721–731PubMedCrossRefGoogle Scholar
  2. 2.
    McEwen BS (2005) Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54(5 Suppl. 1):20–23PubMedCrossRefGoogle Scholar
  3. 3.
    Pacak K, Palkovits M (2001) Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 22:502–548PubMedCrossRefGoogle Scholar
  4. 4.
    Duman RS, Malberg J, Thome J (1999) Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 46:1181–1191PubMedCrossRefGoogle Scholar
  5. 5.
    McIntosh L, Sapolsky R (1996) Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induce toxicity in neuronal culture. Exp Neurol 141:201–206PubMedCrossRefGoogle Scholar
  6. 6.
    Cochrane C (1991) Mechanisms of oxidant injury of cells. Mol Aspects Med 12:137–147PubMedCrossRefGoogle Scholar
  7. 7.
    Anderson DK, Saunders RD, Demediuk P et al (1985) Lipid hydrolysis and peroxidation in injured spinal cord: partial protection with methylprednisolone or vitamin E and selenium. Cent Nerv Syst Trauma 2:257–267PubMedGoogle Scholar
  8. 8.
    Metodiewa D, Koska C (2000) Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxic events and neurologic disorders. An overview. Neurotox Res 1:197–233CrossRefGoogle Scholar
  9. 9.
    Sandhir R, Julka D, Gill KD (1994) Lipoperoxidative damage on lead exposure in rat brain and its implications on membrane bound enzymes. Pharmacol Toxicol 74:66–71PubMedCrossRefGoogle Scholar
  10. 10.
    Bondy SC (1992) Reactive oxygen species: relation to aging and neurotoxic damage. Neurotoxicology 13:87–100PubMedGoogle Scholar
  11. 11.
    Halliwell B, Cross CE (1994) Oxygen-derived species: their relation to human disease and environmental stress. Environ Health Perspect 102:5–12PubMedCrossRefGoogle Scholar
  12. 12.
    Kehrer JP (2000) The Haber–Weiss reaction and mechanisms of toxicity. Toxicology 149:43–50PubMedCrossRefGoogle Scholar
  13. 13.
    McIntosh LJ, Cortopassi KM, Sapolsky RM (1998) Glucocorticoids may alter antioxidant enzyme capacity in the brain: kainic acid studies. Brain Res 791:215–222PubMedCrossRefGoogle Scholar
  14. 14.
    McIntosh LJ, Hong KE, Sapolsky RM (1998) Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies. Brain Res 791:209–214PubMedCrossRefGoogle Scholar
  15. 15.
    Fontella FU, Siqueira IR, Vasconcellos AP et al (2005) Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem Res 30:105–111PubMedCrossRefGoogle Scholar
  16. 16.
    Manji HK, Moore GJ, Chen G (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 46:929–940PubMedCrossRefGoogle Scholar
  17. 17.
    Shaldubina A, Agam G, Belmaker RH (2001) The mechanism of lithium action: state of the art, ten years later. Prog Neuropsychopharmacol Biol Psychiatry 25:855–866PubMedCrossRefGoogle Scholar
  18. 18.
    Chen RW, Chuang DM (1999) Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 274:6039–6042PubMedCrossRefGoogle Scholar
  19. 19.
    Jope RS (1999) Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry 4:117–128PubMedCrossRefGoogle Scholar
  20. 20.
    Manji HK, Moore GJ, Chen G (2000) Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness. J Clin Psychiatry 61(Suppl. 9):82–96PubMedGoogle Scholar
  21. 21.
    Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426PubMedCrossRefGoogle Scholar
  22. 22.
    Schafer M, Goodenough S, Moosmann B et al (2004) Inhibition of glycogen synthase kinase 3 beta is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain Res 1005:84–89PubMedCrossRefGoogle Scholar
  23. 23.
    Pugazhenthi S, Nesterova A, Jambal P et al (2003) Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem 84:982–996PubMedCrossRefGoogle Scholar
  24. 24.
    Hochman A, Sternin H, Gorodin S et al (1998) Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice. J Neurochem 71:741–748PubMedCrossRefGoogle Scholar
  25. 25.
    Vasconcellos AP, Tabajara AS, Ferrari C et al (2003) Effect of chronic stress on spatial memory in rats is attenuated by lithium treatment. Physiol Behav 79:143–149PubMedCrossRefGoogle Scholar
  26. 26.
    Rocha E, Rodnight R (1994) Chronic administration of lithium chloride increases immunodetectable glial fibrillary acidic protein in the rat hippocampus. J Neurochem 63:1582–1584PubMedCrossRefGoogle Scholar
  27. 27.
    Vasconcellos APS, Zugno A, Santos AHDP et al (2005) Na+, K+-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: effect of chronic lithium treatment and possible involvement in learning deficits. Neurobiol Learn Mem 84:102–110PubMedCrossRefGoogle Scholar
  28. 28.
    Konarska M, Stewart RE, McCarty R (1990) Predictability of chronic intermittent stress: effects on sympathetic-adrenal medullary responses of laboratory rats. Behav Neural Biol 53:231–243PubMedCrossRefGoogle Scholar
  29. 29.
    Willner P (1991) Animal models as simulations of depression. Trends Pharmacol Sci 12:131–136PubMedCrossRefGoogle Scholar
  30. 30.
    Murua VS, Molina VA (1992) Effects of chronic variable stress and antidepressant drugs on behavioral inactivity during an uncontrollable stress: interaction between both treatments. Behav Neural Biol 57:87–89PubMedCrossRefGoogle Scholar
  31. 31.
    Gamaro GD, Manoli LP, Torres IL et al (2003) Effects of chronic variate stress on feeding behavior and on monoamine levels in different rat brain structures. Neurochem Int 42:107–114PubMedCrossRefGoogle Scholar
  32. 32.
    Wang IH, Joseph JA (1999) Quantifying cellular oxidative stress by a dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27:612–616PubMedCrossRefGoogle Scholar
  33. 33.
    Buege JA, Aust SD (1987) Microsomal lipid peroxidation. Methods Enzymol 52:302–310Google Scholar
  34. 34.
    Evelson P, Travacio M, Repetto M et al (2001) Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols. Arch Biochem Biophys 388:261–266PubMedCrossRefGoogle Scholar
  35. 35.
    Lissi E, Pascual C, del Castillo MD (1992) Luminol luminescence induced by 2,2′-azo-bis(2-amidinopropane) thermolysis. Free Radic Res Commun 17:299–311PubMedGoogle Scholar
  36. 36.
    Lissi E, Salim-Hanna M, Pascual C et al (1995) Evaluation of total antioxidant potential (TRAP) and total antioxidant reactivity from luminol-enhanced chemiluminescence measurements. Free Radic Biol Med 18:153–158PubMedCrossRefGoogle Scholar
  37. 37.
    Delmas-Beauvieux MC, Peuchant E, Dumon MF et al (1995) Relationship between red blood cell antioxidant enzymatic system status and lipoperoxidation during the acute phase of malaria. Clin Biochem 28:163–169PubMedCrossRefGoogle Scholar
  38. 38.
    Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333PubMedCrossRefGoogle Scholar
  39. 39.
    Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  40. 40.
    LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231PubMedCrossRefGoogle Scholar
  41. 41.
    Orhan H, Gurer-Orhan H, Vriese E et al (2006) Application of lipid peroxidation and protein oxidation biomarkers for oxidative damage in mammalian cells. A comparison with two fluorescent probes. Toxicol In Vitro 20:1005–1013PubMedCrossRefGoogle Scholar
  42. 42.
    Liu J, Wang X, Mori A (1994) Immobilization stress-induced antioxidant defense changes in rat plasma: effect of treatment with reduced glutathione. Int J Biochem 26:511–517PubMedCrossRefGoogle Scholar
  43. 43.
    Oishi K, Yokoi M, Maekawa S et al (1999) Oxidative stress and haematological changes in immobilized rats. Acta Physiol Scand 165:65–69PubMedCrossRefGoogle Scholar
  44. 44.
    Manoli LP, Gamaro GD, Silveira PP et al (2000) Effect of chronic variate stress on thiobarbituric-acid reactive species and on total radical-trapping potential in distinct regions of rat brain. Neurochem Res 25:915–921PubMedCrossRefGoogle Scholar
  45. 45.
    Shao L, Young LT, Wang JF (2005) Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells. Biol Psychiatry 58:879–884PubMedCrossRefGoogle Scholar
  46. 46.
    King TD, Jope RS (2005) Inhibition of glycogen synthase kinase-3 protects cells from intrinsic but not extrinsic oxidative stress. Neuroreport 16:597–601PubMedCrossRefGoogle Scholar
  47. 47.
    Brigelius-Flohe R (1999) Tissue-specific functions of individual glutathione peroxidases. Free Radic Biol Med 27:951–965PubMedCrossRefGoogle Scholar
  48. 48.
    Kielczykowska M, Pasternak K, Musik I et al (2004) The effect of lithium administration in a diet on the chosen parameters of the antioxidant barrier in rats. Ann Univ Mariae Curie Sklodowska [Med] 59:140–145Google Scholar
  49. 49.
    Viggiano A, Viggiano D, Viggiano A et al (2003) Quantitative histochemical assay for superoxide dismutase in rat brain. J Histochem Cytochem 51:865–871PubMedGoogle Scholar
  50. 50.
    Grillo CA, Piroli GG, Rosell DR et al (2003) Region specific increases in oxidative stress and superoxide dismutase in the hippocampus of diabetic rats subjected to stress. Neuroscience 121:133–140PubMedCrossRefGoogle Scholar
  51. 51.
    Bemeur C, Ste-Marie L, Desjardins P et al (2004) Expression of superoxide dismutase in hyperglycemic focal cerebral ischemia in the rat. Neurochem Int 45:1167–1174PubMedCrossRefGoogle Scholar
  52. 52.
    Noack H, Lindenau J, Rothe F et al (1998) Differential expression of superoxide dismutase isoforms in neuronal and glial compartments in the course of excitotoxically mediated neurodegeneration: relation to oxidative and nitrergic stress. Glia 23:285–297PubMedCrossRefGoogle Scholar
  53. 53.
    Levine S, Saltzman A (2006) Lithium increases body weight of rats: relation to thymolysis. Prog Neuropsychopharmacol Biol Psychiatry 30:155–158PubMedCrossRefGoogle Scholar
  54. 54.
    Husum H, Mathe AA (2002) Early life stress changes concentrations of neuropeptide Y and corticotropin-releasing hormone in adult rat brain. Lithium treatment modifies these changes. Neuropsychopharmacology 27:756–764PubMedCrossRefGoogle Scholar
  55. 55.
    Esposito P, Gheorghe D, Kandere K et al (2001) Acute stress increases permeability of the blood–brain-barrier through activation of brain mast cells. Brain Res 888:117–127PubMedCrossRefGoogle Scholar
  56. 56.
    Calingasan NY, Park LC, Calo LL et al (1998) Induction of nitric oxide synthase and microglial responses precede selective cell death induced by chronic impairment of oxidative metabolism. Am J Pathol 153:599–610PubMedGoogle Scholar
  57. 57.
    Gong L, Wyatt RJ, Baker I et al (1999) Brain-derived and glial cell line-derived neurotrophic factors protect a catecholaminergic cell line from dopamine-induced cell death. Neurosci Lett 263:153–156PubMedCrossRefGoogle Scholar
  58. 58.
    Ikeda O, Murakami M, Ino H et al (2002) Effects of brain-derived neurotrophic factor (BDNF) on compression-induced spinal cord injury: BDNF attenuates down-regulation of superoxide dismutase expression and promotes up-regulation of myelin basic protein expression. J Neuropathol Exp Neurol 61:142–153PubMedGoogle Scholar
  59. 59.
    Manji HK, Duman RS (2001) Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 35:5–49PubMedGoogle Scholar
  60. 60.
    Ceballos-Picot I, Nicole A, Clement M et al (1992) Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper–zinc superoxide dismutase. Mutat Res 275:281–293PubMedGoogle Scholar
  61. 61.
    Erakovic V, Zupan G, Varljen J et al (2000) Lithium plus pilocarpine induced status epilepticus—biochemical changes. Neurosci Res 36:157–166PubMedCrossRefGoogle Scholar
  62. 62.
    Masella R, Di Benedetto R, Vari R et al (2005) Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 16:577–586PubMedCrossRefGoogle Scholar
  63. 63.
    Wesbrot-Lefkowitz M, Reuhl K, Perry B et al (1998) Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage. Mol Brain Res 53:333–338CrossRefGoogle Scholar
  64. 64.
    Michiels C, Raes M, Toussaint O et al (1994) Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress. Free Radic Biol Med 17:235–248PubMedCrossRefGoogle Scholar
  65. 65.
    Prediger ME, Gamaro GD, Crema LM et al (2004) Estradiol protects against oxidative stress induced by chronic variate stress. Neurochem Res 29:1923–1930PubMedCrossRefGoogle Scholar
  66. 66.
    Graumann R, Paris I, Martinez-Alvarado P et al (2002) Oxidation of dopamine to aminochrome as a mechanism for neurodegeneration of dopaminergic systems in Parkinson’s disease. Possible neuroprotective role of DT-diaphorase. Pol J Pharmacol 54:573–579Google Scholar
  67. 67.
    Benkovic SA, Connor JR (1993) Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. Neurology 338:97–113Google Scholar
  68. 68.
    Focht SJ, Snyder BS, Beard JL et al (1997) Regional distribution of iron, transferrin, ferritin, and oxidatively-modified proteins in young and aged Fischer 344 rat brains. Neuroscience 79:255–261PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Ana Paula Santana de Vasconcellos
    • 1
    • 2
  • Fabiane Battistela Nieto
    • 2
  • Leonardo Machado Crema
    • 1
  • Luisa Amália Diehl
    • 2
  • Lúcia Maria de Almeida
    • 2
  • Martha Elisa Prediger
    • 2
  • Elizabete Rocha da Rocha
    • 1
    • 2
  • Carla Dalmaz
    • 1
    • 2
  1. 1.Programa de Pós-Graduação em NeurociênciasInstituto de Ciências Básicas da Saúde, UFRGSPorto AlegreBrazil
  2. 2.Departamento de BioquímicaInstituto de Ciências Básicas da Saúde, UFRGSPorto AlegreBrazil

Personalised recommendations