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Clomipramine Treatment and Repeated Restraint Stress Alter Parameters of Oxidative Stress in Brain Regions of Male Rats

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Abstract

This study aimed to compare the effects of repeated restraint stress alone and the combination with clomipramine treatment on parameters of oxidative stress in cerebral cortex, striatum and hippocampus of male rats. Animals were divided into control and repeated restraint stress, and subdivided into treated or not with clomipramine. After 40 days of stress and 27 days of clomipramine treatment with 30 mg/kg, the repeated restraint stress alone reduced levels of Na+, K+-ATPase in all tissues studied. The combination of repeated restraint stress and clomipramine increased the lipid peroxidation, free radicals and CAT activity as well as decreased levels of NP-SH in the tissues studied. However, Na+, K+-ATPase level decreased in striatum and cerebral cortex and the SOD activity increased in hippocampus and striatum. Results indicated that clomipramine may have deleterious effects on the central nervous system especially when associated with repeated restraint stress and chronically administered in non therapeutic levels.

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References

  1. Sapolsky RM (2000) Stress hormones: good and bad. Neurobiol Dis 7:540–542

    Article  CAS  PubMed  Google Scholar 

  2. Leonard BE, Song C (1996) Stress and the immune system in the etiology of anxiety and depression. Pharmacol Biochem Behav 54:299–303

    Article  CAS  PubMed  Google Scholar 

  3. McEwen BS, Sapolsky RM (1995) Stress and cognitive function. Curr Opin Neurobiol 5:205–216

    Article  CAS  PubMed  Google Scholar 

  4. Fontella FU, Siqueira IR, Vasconcellos APS et al (2005) Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem Res 30:105–111

    Article  CAS  PubMed  Google Scholar 

  5. McIntosh L, Sapolsky R (1996) Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induce toxicity in neuronal culture. Exp Neurol 141:201–206

    Article  CAS  PubMed  Google Scholar 

  6. Seckl JR, Dickson KL, Fink G (1990) Central 5–7 dihydroxytryptamine lesions decrease hippocampal glucocorticoid and mineralocorticoid receptor messenger ribonucleic acid expression. J Neuroendocrinol 2:911–916

    Article  CAS  PubMed  Google Scholar 

  7. Fuchs E, Kramer M, Hermes B et al (1996) Psychosocial stress in tree shrews: clomipramine counteracts behavioral and endocrine changes. Pharmacol Biochem Behav 54:219–228

    Article  CAS  PubMed  Google Scholar 

  8. Demerdash EE, Mohamadin AM (2004) Does oxidative stress contribute in tryciclic antidepressants-induced cardiotoxicity. Toxicol Lett 152:159–166

    PubMed  Google Scholar 

  9. Potter WZ, Manji HK, Rudorfer MV (1998) Tricyclics and tetracyclics. In: Schatzberg AF, Nemeroff CB (eds) Textbooks of psychopharmacology. American Psychiatric Press, UK, pp 199–218

    Google Scholar 

  10. Rudorfer MV, Manji HK, Potter WZ (1994) Comparative tolerability profiles of the newer versus older antidepressants. Drug Saf 10:18–46

    Article  CAS  PubMed  Google Scholar 

  11. Peters MD, Davies SK, Austin S (1990) Clomipramine: an antiobsessional tricyclic antidepressant. Clin Pharm 9:165–178

    CAS  PubMed  Google Scholar 

  12. Trimble MR (1990) Worldwide use of clomipramine. J Clin Psychiatry 51:51–54

    PubMed  Google Scholar 

  13. Bhagya V, Srikumar BN, Raju TR et al (2008) Neonatal clomipramine induced endogenous depression in rats is associated with learning impairment in adulthood. Behav Brain Res 187:190–194

    Article  CAS  PubMed  Google Scholar 

  14. Srikumar BN, Raju TR, Shankaranarayana Rao BS (2006) The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed rats. Neuroscience 143:679–688

    Article  CAS  PubMed  Google Scholar 

  15. D’Aquila PS, Peana AT, Carboni V et al (2000) Exploratory behaviour and grooming after repeated restraint and chronic mild stress: effect of desipramine. Eur J Pharmacol 399:43–47

    Article  PubMed  Google Scholar 

  16. Consoli D, Fedotova J, Micale V (2005) Stressors affect the response of male and female rats to clomipramine in a model of behavioral despair (forced swim test). Eur J Phamacol 520:100–107

    Article  CAS  Google Scholar 

  17. Calegari L, Gorenstein C, Gentil V (2007) Effect of chronic treatment with clomipramine on food intake, macronutrient selection and body weight gain in rats. Biol Pharm Bull 30:1541–1546

    Article  CAS  PubMed  Google Scholar 

  18. Ely DR, Dapper V, Marasca J (1997) Effect of restraint stress on feeding behavior of rats. Phisiol Behav 61:395–398

    Article  CAS  Google Scholar 

  19. Lucassen PJ, Fuchs E, Czeh B (2004) Antidepressant treatment with tianeptine reduces apoptosis in the hippocampal dentate gyrus and temporal cortex. Biol Psychiatry 55:789–796

    Article  CAS  PubMed  Google Scholar 

  20. Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine, 4th edn. Oxford University Press, New York

    Google Scholar 

  21. Ohkawa H, Ohishi N, Yagy K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  22. Ellman GL (1952) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  Google Scholar 

  23. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  24. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and simple assay for superoxide dismutase. J Biol Chem 247:3170–3175

    CAS  PubMed  Google Scholar 

  25. Muszbek L (1997) A highly sensitive method for the measurement of the ATP-ase activity. Anal Biochem 77:286–288

    Article  Google Scholar 

  26. Atkinson A, Gatenby AD, Lowe AG (1973) The determination of inorganic orthophosphate in biological systems. Biochim Biophys Acta 320:195–204

    CAS  PubMed  Google Scholar 

  27. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  28. Prediger ME, Gamaro GD, Crema LM et al (2004) Estradiol protects against oxidative stress induced by chronic variate stress. Neurochem Res 29:1923–1930

    Article  CAS  PubMed  Google Scholar 

  29. Juruena MF, Cleare AJ, Pariante CM (2004) The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr 26:189–201

    Article  PubMed  Google Scholar 

  30. De Vasconcellos APS, Nieto FB, Crema LM et al (2006) Chronic lithium treatment has properties but do not prevent oxidative damage induced by chronic variate stress. Neurochem Res 31:1141–1151

    Article  CAS  PubMed  Google Scholar 

  31. Aitchison K, Datla K, Rooprai H et al (2009) Regional distribution of clomipramine and desmethyllomipramine in rat brain and peripheral organs on chronic clomipramine administration. J Psychopharmacol 1–8

  32. Gamaro GD, Manoli LP, Torres IL et al (2003) Effects of chronic variate stress on feeding behavior and monoamine levels in different rat brain structures. Neurochem Int 42:107–114

    Article  CAS  PubMed  Google Scholar 

  33. 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 54:573–579

    CAS  PubMed  Google Scholar 

  34. Whyte IM, Buckley NA (1995) Relative toxicity and resource utilization in antidepressant self poisoning: tricyclics vs specific serotonin reuptake inhibitors. Proc Australas Soc Clin Exp Pharmacol Toxicol 2:103

    Google Scholar 

  35. Lai M, McCormick JA, Chapman KE et al (2003) Differential regulation of corticosteroid receptors by monoamine neurotransmitters and antidepressant drugs in primary hippocampal culture. Neuroscience (in press)

  36. Pariante CM, Pearce BD, Pisell TL et al (1997) Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. Mol Pharmacol 52:571–581

    CAS  PubMed  Google Scholar 

  37. Pariante CM, Makoff A, Lovestone S et al (2001) Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters. Br J Pharmacol 134:1335–1343

    Article  CAS  PubMed  Google Scholar 

  38. Carvalho LA, Juruena MF, Papadopulos AS et al (2008) Clomipramine in vitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression. Neuropsychopharmacology 33:3182–3189

    Article  CAS  PubMed  Google Scholar 

  39. Carvalho LA, Garner BA, Dew T et al (2010) Antidepressants, but not antipsychotics, modulate GR function in humans whole blood: an Insight into molecular mechanisms. Eur Neuropsychopharmacol (in press)

  40. 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 20:1005–1013

    Article  CAS  PubMed  Google Scholar 

  41. Zafir A, Ara A, Banu N (2009) In vivo antioxidant status: a putative target of antidepressant action. Neuro-Psychopharmacol Biol Psych 33:220–228

    Article  CAS  Google Scholar 

  42. Pal SN, Dandiya PC (1994) Glutathione as a cerebral substrate in depressive behavior. Pharmacol Biochem Behav 48:845–851

    Article  CAS  PubMed  Google Scholar 

  43. Gilberti EA, Trombetta LD (2000) The relationship between stress protein induction and the oxidative defense system in the rat hippocampus following kainic acid administration. Toxicol Lett 116:17–26

    Article  CAS  PubMed  Google Scholar 

  44. Saija A, Princi P, Paisini A et al (1994) Protective effect of glutathione on kainic acid–induced neuropathological changes in the rat brain. Gen Pharmacol 25:97–102

    CAS  PubMed  Google Scholar 

  45. Abraham IM, Harkany T, Horvath KM et al (2001) Action of glucocorticoids on survival of nerve cells: promoting neurodegeneration or neuroprotection. Neuroendocrinology 13:749–760

    CAS  Google Scholar 

  46. Patel R, McIntosh L, McLaughlin J et al (2002) Disruptive effects of glucocorticoids on glutathione peroxidase biochemistry in hippocampal cultures. J Neurochem 82:118–125

    Article  CAS  PubMed  Google Scholar 

  47. Mattson MP (1998) Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci 20:53–57

    Article  Google Scholar 

  48. Xiong ZQ, Stringer JL (2000) Sodium pump activity, not glial spatial buffering, clears potassium after epileptiform activity induced in the dentate gyrus. J Neurophysiol 83:1443–1451

    CAS  PubMed  Google Scholar 

  49. Zanatta LM, Nascimento FC, Barros SV et al (2001) In vivo and in vitro effect of imipramine and fluoxetine on Na+, K+-ATPase activity in synaptic plasma membranes from the cerebral cortex of rats. Braz J Med Biol Res 34:1265–1269

    Article  CAS  PubMed  Google Scholar 

  50. Pedrazza EL, Senger MR, Pedrazza L (2007) Sertraline and clomipramine inhibit nucleotide catabolism in rat brain synaptosomes. Toxicol In Vitro 21:671–676

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the FINEP research grant “Rede Instituto Brasileiro de Neurociência (IBN-Net)” # 01.06.0842-00 and INCT for Excitotoxicity and Neuroprotection- MCT/CNPq.

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Correspondence to Felix Alexandre Antunes Soares.

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de Souza Balk, R., Bridi, J.C., de Lima Portella, R. et al. Clomipramine Treatment and Repeated Restraint Stress Alter Parameters of Oxidative Stress in Brain Regions of Male Rats. Neurochem Res 35, 1761–1770 (2010). https://doi.org/10.1007/s11064-010-0240-1

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  • DOI: https://doi.org/10.1007/s11064-010-0240-1

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