Metabolic Brain Disease

, Volume 29, Issue 1, pp 185–192 | Cite as

Omega-3 fatty acids alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration

  • Camila S. Model
  • Lara M. Gomes
  • Giselli Scaini
  • Gabriela K. Ferreira
  • Cinara L. Gonçalves
  • Gislaine T. Rezin
  • Amanda V. Steckert
  • Samira S. Valvassori
  • Roger B. Varela
  • João Quevedo
  • Emilio L. Streck
Original Paper

Abstract

Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidences indicate that omega-3 (ω3) fatty acids play several important roles in brain development and functioning. Moreover, preclinical and clinical evidence suggests roles for ω3 fatty acids in BD. Considering these evidences, the present study aimed to investigate the effects of ω3 fatty acids on locomotor behavior and oxidative stress parameters (TBARS and protein carbonyl content) in brain of rats subjected to an animal model of mania induced by fenproporex. The fenproporex treatment increased locomotor behavior in saline-treated rats under reversion and prevention model, and ω3 fatty acids prevented fenproporex-related hyperactivity. Moreover, fenproporex increased protein carbonyls in the prefrontal cortex and cerebral cortex, and the administration of ω3 fatty acids reversed this effect. Lipid peroxidation products also are increased in prefrontal cortex, striatum, hippocampus and cerebral after fenproporex administration, but ω3 fatty acids reversed this damage only in the hippocampus. On the other hand, in the prevention model, fenproporex increased carbonyl content only in the cerebral cortex, and administration of ω3 fatty acids prevented this damage. Additionally, the administration of fenproporex resulted in a marked increased of TBARS in the prefrontal cortex, hippocampus, striatum and cerebral cortex, and prevent this damage in the prefrontal cortex, hippocampus and striatum. In conclusion, we are able to demonstrate that fenproporex-induced hyperlocomotion and damage through oxidative stress were prevented by ω3 fatty acids. Thus, the ω3 fatty acids may be important adjuvant therapy of bipolar disorder.

Keywords

Bipolar disorder Fenproporex Omega-3 fatty acids Oxidative stress 

References

  1. Anand A, Verhoeff P, Seneca N et al (2000) Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients. Am J Psychiatry 157:1108–1114PubMedCrossRefGoogle Scholar
  2. Andreazza AC, Cassini C, Rosa AR et al (2007) Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 41:523–529PubMedCrossRefGoogle Scholar
  3. Andreazza AC, Wang JF, Salmasi F et al (2013) Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder. J Neurochem. doi:10.1111/jnc.12316 PubMedGoogle Scholar
  4. Balanzá-Martínez V, Fries GR, Colpo GD et al (2011) Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert Rev Neurother 11:1029–1047PubMedCrossRefGoogle Scholar
  5. Barros DM, Izquierdo LA, Medina JH, Izquierdo I (2002) Bupropion and sertraline enhance retrieval of recent and remote long-term memory in rats. Behav Pharmacol 13:215–220PubMedCrossRefGoogle Scholar
  6. Bas O, Songur A, Sahin O et al (2007) The protective effect of fish n-3 fatty acids on cerebral ischemia in rat hippocampus. Neurochem Int 503:548–554CrossRefGoogle Scholar
  7. Bazan NG (2009) Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer’s disease. J Lipid Res 50:S400–S405PubMedCrossRefGoogle Scholar
  8. Belmaker RH (2004) Bipolar disorder. N Engl J Med 351:476–486PubMedCrossRefGoogle Scholar
  9. Berger GE, Wood SJ, Wellard RM et al (2008) Ethyl-eicosapentaenoic acid in first-episode psychosis. A 1H-MRS study. Neuropsychopharmacology 33:2467–2473PubMedCrossRefGoogle Scholar
  10. Berk M, Kapczinski F, Andreazza AC et al (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35:804–817PubMedCrossRefGoogle Scholar
  11. Bielau H, Brisch R, Bernard-Mittelstaedt J et al (2012) Immunohistochemical evidence for impaired nitric oxide signaling of the locus coeruleus in bipolar disorder. Brain Res 1459:91–99PubMedCrossRefGoogle Scholar
  12. Bird RP, Draper AH (1984) Comparative studies on different methods of malondyhaldehyde determination. Methods Enzymol 105:299–05PubMedCrossRefGoogle Scholar
  13. Clay HB, Sillivan S, Konradi C (2011) Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 29:311–324PubMedCentralPubMedCrossRefGoogle Scholar
  14. Cody JT, Valtier S, Stillman S (1999) Amphetamine and fenproporex levels following multidose administration of fenproporex. J Ana Toxicol 23:187–194CrossRefGoogle Scholar
  15. Coutts RT, Nazarali AJ, Baker GB, Pasutto FM (1986) Metabolism and disposition of N-(2-cyanoethyl) amphetamine (fenproporex) andamphetamine: study in the rat brain. Can J Physiol Pharmacol 64:724–728PubMedCrossRefGoogle Scholar
  16. Du Bois TM, Deng C, Bell W, Huang XF (2006) Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. Neurosc 139:1397–03CrossRefGoogle Scholar
  17. El-Ansary AK, Al-Daihan SK, El-Gezeery AR (2011) On the protective effect of omega-3 against propionic acid-induced neurotoxicity in rat pups. Lipids Health Dis 10:142PubMedCentralPubMedCrossRefGoogle Scholar
  18. El-Mallakh RS, El-Masri MA, Huff MO et al (2003) Intracerebroventricular administration of ouabain as a model of mania in rats. Bipolar Disord 5:362–365PubMedCrossRefGoogle Scholar
  19. Ericson E, Samuelsson J, Ahlenius S (1991) Photocell measurements of rat motor activity. A contribution to sensitivity and variation in behavioral observations. Journal of Pharmacological Methods 25:111–122PubMedCrossRefGoogle Scholar
  20. Frey BN, Martins MR, Petronilho FC et al (2006a) Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania. Bipolar Disord 8:275–280CrossRefGoogle Scholar
  21. Frey BN, Valvassori SS, Réus GZ et al (2006b) Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci 31:326–332Google Scholar
  22. Frey BN, Valvassori SS, Réus GZ et al (2006c) Changes in antioxidant defense enzymes after d-amphetamine exposure: implications as an animal model of mania. Neurochem Res 31:699–703CrossRefGoogle Scholar
  23. Frey BN, Andreazza AC, Kunz M et al (2007) Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report. Prog Neuropsychopharmacol Biol Psychiatry 31:283–295PubMedCrossRefGoogle Scholar
  24. Gama CS, Canever L, Panizzutti B et al (2012) Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: a study in adolescent rats with ketamine-induced model of schizophrenia. Schizophr Res 141:162–167PubMedCrossRefGoogle Scholar
  25. Gawryluk JW, Wang JF, Andreazza AC et al (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14:123–130PubMedCrossRefGoogle Scholar
  26. Gigante AD, Andreazza AC, Lafer B et al (2011) Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia. Neurosci Lett 505:47–51PubMedCrossRefGoogle Scholar
  27. Gleissman H, Johnsen JI, Kogner P (2010) Omega-3 fatty acids in cancer, the protectors of good and the killers of evil? Exp Cell Res 316:1365–1373PubMedCrossRefGoogle Scholar
  28. Gonda X, Pompili M, Serafini G et al (2012) Suicidal behavior in bipolar disorder: Epidemiology, characteristics and major risk factors. J Affect Disord 143:16–26PubMedCrossRefGoogle Scholar
  29. Goodwin FK, Jamison KR (1990) Manic-Depressive Illness: Second Edition New York. Oxford University Press, NYGoogle Scholar
  30. Guest J, Garg M, Bilgin A, Grant R (2013) Relationship between central and peripheral fatty acids in humans. Lipids Health Dis 12:79PubMedCentralPubMedCrossRefGoogle Scholar
  31. Haag M (2003) Essential fatty acids and the brain. Can J Psychiatry 48:195–203PubMedGoogle Scholar
  32. Jana S, Sinha M, Chanda D et al (2011) Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson’s disease. Biochim Biophys Acta 1812:663–673PubMedCrossRefGoogle Scholar
  33. Kapczinski F, Dal-Pizzol F, Teixeira AL et al (2011) Peripheral biomarkers and illness activity in bipolar disorder. J Psychiatr Res 45:156–161PubMedCrossRefGoogle Scholar
  34. Kato T, Kato N (2000) Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2:180–190PubMedCrossRefGoogle Scholar
  35. Katsumata T, Katayama Y, Obo R et al (1999) Delayed administration of ethyl eicosapentate improves local cerebral blood flow and metabolism without affecting infarct volumes in the rat focal ischemic model. Eur J Pharmacol 372:167–174PubMedCrossRefGoogle Scholar
  36. Kishi T, Yoshimura R, Fukuo Y et al (2013) The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci 263:105–118PubMedCrossRefGoogle Scholar
  37. Kitajka K, Sinclair AJ, Weisinger RS et al (2004) Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci U S A 101:10931–10936PubMedCentralPubMedCrossRefGoogle Scholar
  38. Konradi C, Eaton M, Macdonald ML et al (2004) Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 61:300–308PubMedCrossRefGoogle Scholar
  39. Kraemer T, Theis GA, Weber AA, Maurer HH (2000) Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography–mass spectrometry and fluorescence polarization immunoassay. J Chromatogr B 738:107–118CrossRefGoogle Scholar
  40. Kuloglu M, Ustundag B, Atmaca M et al (2002) Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem and Function 20:171–175CrossRefGoogle Scholar
  41. Kunz M, Gama CS, Andreazza AC et al (2008) Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32:1677–1681PubMedCrossRefGoogle Scholar
  42. Lai YL, Rodarte JR, Hyatt RE (1977) Effect of body position on lung emptying in recumbent anesthetized dogs. J Appl Physiol 43:983–987PubMedGoogle Scholar
  43. Lavialle M, Champeil-Potokar G, Alessandri JM et al (2008) An (n-3) polyunsaturated fatty acid-deficient diet disturbs daily locomotor activity, melatonin rhythm, and striatal dopamine in Syrian hamsters. J Nutr 138:1719–1724PubMedGoogle Scholar
  44. Leclerc E, Mansur RB, Brietzke E (2013) Determinants of adherence to treatment in bipolar disorder: A comprehensive review. J Affect Disord 149:247–252PubMedCrossRefGoogle Scholar
  45. Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357PubMedCrossRefGoogle Scholar
  46. Logan AC (2003) Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression. Altern Med Rev 8:410–425PubMedGoogle Scholar
  47. Machado-Vieira R, Kapczinski F, Soares JC (2004) Perspective for the development of animals models of bipolar disorders. Prog NeuroPsycopharmacol Biol Psychiatry 28:209–224CrossRefGoogle Scholar
  48. Mattei R, Carlini EA (1996) A comparative study of the anorectic and behavioral effects of fenproporex on male and female rats. Braz J Med Biol Res 29:1025–1030PubMedGoogle Scholar
  49. Mossaheb N, Schäfer MR, Schlögelhofer M et al (2013) Effect of omega-3 fatty acids for indicated prevention of young patients at risk for psychosis: When do they begin to be effective? Schizophr Res. doi:10.1016/j.schres.2013.05.027 Google Scholar
  50. Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169PubMedCentralPubMedCrossRefGoogle Scholar
  51. Noaghiul S, Hibbeln JR (2003) Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry 160:2222–2227PubMedCrossRefGoogle Scholar
  52. Ozyurt B, Sarsilmaz M, Akpolat N et al (2007) The protective effects of omega-3 fatty acids against MK-801-induced neurotoxicity in prefrontal cortex of rat. Neurochem Int 50:196–202PubMedCrossRefGoogle Scholar
  53. Pinsonneault JK, Han DD, Burdick KE et al (2011) Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology 36:1644–1655PubMedCrossRefGoogle Scholar
  54. Piomelli D (1994) Eicosanoids in synaptic transmission. Crit Rev Neurbiol 8:65–83Google Scholar
  55. Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33PubMedCrossRefGoogle Scholar
  56. Quiroz JA, Gray NA, Kato T, Manji HK (2008) Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33:2551–2565PubMedCrossRefGoogle Scholar
  57. Rajkowska G (2002) Cell pathology in bipolar disorder. Bipolar Disord :4105-16Google Scholar
  58. Rao JS, Lee HJ, Rapoport SI, Bazinet RP (2008) Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? Mol Psychiatry 13:585–596PubMedCrossRefGoogle Scholar
  59. Rezin GT, Furlanetto CB, Scaini G, et al. (2013) Fenproporex increases locomotor activity, alters energy metabolism and mood stabilizers reverse these changes: a proposal for a new animal model of mania. Molecular Neurobiology, in press.Google Scholar
  60. Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491–8497PubMedGoogle Scholar
  61. Sagduyu K, Dokucu ME, Eddy BA et al (2005) Omega-3 fatty acids decreased irritability of patients with bipolar disorder in an add-on, open label study. Nutr J 4:1–6CrossRefGoogle Scholar
  62. Salem N Jr, Litman B, Kim HY, Gawrish K (2001) Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36:945–959PubMedCrossRefGoogle Scholar
  63. Salomone JD, Cousins MS, Snyder BJ (1997) Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci Biobehav Ver 21:341–359CrossRefGoogle Scholar
  64. Serhan CN, Yacoubian S, Yang R (2008) Anti-inflammatory and proresolving lipid mediators. Annu Rev Pathol 3:279–312PubMedCentralPubMedCrossRefGoogle Scholar
  65. Severino G, Squassina A, Costa M et al (2013) Pharmacogenomics of bipolar disorder. Pharmacogen 14:655–674CrossRefGoogle Scholar
  66. Siegel G, Ermilov E (2012) Omega-3 fatty acids: benefits for cardio-cerebro-vascular diseases. Atheroscler 225:291–295CrossRefGoogle Scholar
  67. Sims DE (1991) Recent advances in pericyte biology–implications for health and disease. Can J Cardiol 7:431–443PubMedGoogle Scholar
  68. Sinclair AJ, Begg D, Mathai M, Weisinger RS (2007) Omega 3 fatty acids and the brain: review of studies in depression. Asia Pac J Clin Nutr 16:391–397PubMedGoogle Scholar
  69. Sogaard R, Werge TM, Bertelsen C et al (2006) GABA(A) receptor function is regulated by lipid bilayer elasticity. Biochemistry 45:13118–13129PubMedCrossRefGoogle Scholar
  70. Sonnewald U, Hertz L, Schousboe A (1998) Mitochondrial heterogeneity in the brain at the cellular level. J Cereb Blood Flow Metab 18:231–237PubMedCrossRefGoogle Scholar
  71. Soreca I, Frank E, Kupfer DJ (2009) The phenomenology of bipolar disorder: what drives the high rate of medical burden and determines long-term prognosis? Depress Anxiety 26:73–82PubMedCentralPubMedCrossRefGoogle Scholar
  72. Sosa V, Molin’e T, Somoza T et al (2012) Oxidative stress and cancer: an overview. Ageing Research Review 12:376–390CrossRefGoogle Scholar
  73. Steckert AV, Valvassori SS, Moretti M et al (2010) Role of oxidative stress in the pathophysiology of bipolar disorder. Neurochem Res 35:1295–1301PubMedCrossRefGoogle Scholar
  74. Stoll AL, Severus WE, Freeman MP et al (1999) Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56:407–412PubMedCrossRefGoogle Scholar
  75. Strakowski SM, Sax KW (1998) Progressive behavioral response to repeated Damphetamine challenge: further evidence for sensitization in humans. Biol Psychiatry 44:1171–1177PubMedCrossRefGoogle Scholar
  76. Vawter MP, Tomita H, Meng F et al (2006) Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Molecular psychiatry 11:663–679CrossRefGoogle Scholar
  77. Wall R, Ross RP, Fitzgerald GF, Stanton C (2010) Fatty acids from fish: the antiinflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 68:280–289PubMedCrossRefGoogle Scholar
  78. Wang JF, Shao L, Sun X, Young LT (2009) Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disord 11:523–529PubMedCrossRefGoogle Scholar
  79. Wu A, Ying Z, Gomez-Pinilla F (2004) Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 21:1457–1467PubMedCrossRefGoogle Scholar
  80. Wu A, Ying Z, Gomez-Pinilla F (2008) Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neurosci 155:751–759CrossRefGoogle Scholar
  81. Wultz B, Sagvolden T, Moser EI, Moser MB (1990) The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. Behav Neural Biol 53:88–102PubMedCrossRefGoogle Scholar
  82. Young G, Conquer J (2005) Omega-3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev 45:1–28PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Camila S. Model
    • 1
    • 3
    • 4
  • Lara M. Gomes
    • 1
    • 3
    • 4
  • Giselli Scaini
    • 1
    • 3
    • 4
  • Gabriela K. Ferreira
    • 1
    • 3
    • 4
  • Cinara L. Gonçalves
    • 1
    • 3
    • 4
  • Gislaine T. Rezin
    • 1
    • 3
    • 4
  • Amanda V. Steckert
    • 2
    • 3
    • 4
  • Samira S. Valvassori
    • 2
    • 3
    • 4
  • Roger B. Varela
    • 2
    • 3
    • 4
  • João Quevedo
    • 2
    • 3
    • 4
  • Emilio L. Streck
    • 1
    • 3
    • 4
    • 5
  1. 1.Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  2. 2.Laboratório de Neurociências, Programa de Pós-graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  3. 3.Instituto Nacional de Ciência e Tecnologia Translacional em MedicinaPorto AlegreBrazil
  4. 4.Center of Excellence in in Applied Neuroscience of Santa Catarina (NENASC)FlorianópolisBrazil
  5. 5.Laboratório de BioenergéticaUniversidade do Extremo Sul CatarinenseCriciúmaBrazil

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