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Depressive-Like Parameters in Sepsis Survivor Rats

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Abstract

The inflammatory and immune responses evoked in sepsis may create not only an acute brain dysfunction, which occurs in the majority of septic patients, but also long-term deficits such as memory impairment. In this context, we evaluated depressive-like parameters in sepsis survivor rats. For this purpose, male Wistar rats, weighing 300–350 g, underwent cecal ligation and perforation (CLP) (sepsis group) followed by “basic support”, or were sham-operated (control group). After 3 days of the sepsis procedure, the animals were treated with imipramine at 10 mg/kg or saline during 14 days (days 3–17). The consumption of sweet food was measured for 7 days (days 10–17) and the body weight was measured before CLP, 10, and 17 days after CLP. Seventeen days after sepsis (immediately after sweet food consumption measurement), the animals were anesthetized and blood was withdrawn for the analyses of corticosterone and adrenocorticotropic hormone (ACTH) levels, and immediately killed by decapitation. The adrenal gland and hippocampus were immediately isolated and weighed, and the hippocampus was utilized for determining brain-derived neurotrophic factor (BDNF) levels. It was observed that animals subjected to CLP presented decreased sucrose intake. Septic rats did not increase body weight and presented an increase in the weight of adrenal gland. Both corticosterone and ACTH levels were increased, while hippocampus weight and BDNF levels in the hippocampus decreased. The treatment with imipramine reversed all the parameters described above. Our results supported the hypothesis that rats that survive sepsis show depressive-like behavior, alterations in the hypothalamus–pituitary–adrenal axis, and decreased BDNF levels in the hippocampus.

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References

  • Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310

    Article  CAS  PubMed  Google Scholar 

  • Bergström A, Jayatissa MN, Mørk A, Wiborg O (2008) Stress sensitivity and resilience in the chronic mild stress rat model of depression; an in situ hybridization study. Brain Res 1196:41–52

    Article  PubMed  CAS  Google Scholar 

  • Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125

    Article  CAS  PubMed  Google Scholar 

  • Castren E, Voikar V, Rantamaki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21

    Article  CAS  PubMed  Google Scholar 

  • Chao CC, Hu S, Peterson PK (1995) Glia, cytokines, and neurotoxicity. Crit Rev Neurobiol 9:189–205

    CAS  PubMed  Google Scholar 

  • Comim CM, Rezin GT, Scaini G, Di-Pietro PB, Cardoso MR, Petronilho FC, Ritter C, Streck EL, Quevedo J, Dal-Pizzol F (2008) Mitochondrial respiratory chain and creatine kinase activities in rat brain after sepsis induced by cecal ligation and perforation. Mitochondrion 8:313–318

    Article  CAS  PubMed  Google Scholar 

  • Conner JM, Lauterborn JC, Yan Q, Gall CM, Varon S (1997) Distribution of brainderived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci 17:2295–2313

    CAS  PubMed  Google Scholar 

  • Dess NK, Raizer J, Chapmen CD, Garcia J (1988) Stressors in the learned helplessness paradigm: effects on body weight and conditioned taste aversion in rats. Physiol Behav 44:483–490

    Article  CAS  PubMed  Google Scholar 

  • Dhabhar FS (2001) Acute stress enhances while chronic stress suppresses skin immunity. The role of stress and leukocyte trafficking. Ann N Y Acad Sci 97:2846–2851

    Google Scholar 

  • Dowing JEG, Miyan JA (2000) Neural immunoregulation: emerging roles for nerves in immune homeostasis and disease. Immunol Today 21:281–289

    Article  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorder. Biol Psychiatry 59:1116–1127

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606

    CAS  PubMed  Google Scholar 

  • Eskandari FE, Sternberg EM (2002) Neural-immune interactions in health and disease. Ann N Y Acad Sci 966:20–27

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Garcia LS, Comim CM, Valvassori SS, Réus GZ, Stertz L, Kapczinski F, Gavioli EC, Quevedo J (2009) Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 33:450–455

    Article  CAS  PubMed  Google Scholar 

  • Gillespie CF, Nemeroff CB (2005) Hypercortisolemia and depression. Psychosom Med 67:26–28

    Article  Google Scholar 

  • Givalois L, Marmigère F, Rage F, Ixart G, Arancibia S, Tapia-Arancibia L (2001) Immobilization stress rapidly and differentially modulates BDNF and TrkB mRNA expression in the pituitary gland of adult male rats. Neuroendocrinology 74:148–159

    Article  CAS  PubMed  Google Scholar 

  • Givalois L, Naert G, Rage F, Ixart G, Arancibia S, Tapia-Arancibia L (2004) A single brain-derived neurotrophic factor injection modifies hypothalamo-pituitary-adrenocortical axis activity in adult male rats. Mol Cell Neurosci 27:280–295

    CAS  PubMed  Google Scholar 

  • Grønli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B, Ursin R, Portas CM (2006) Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav 85:842–849

    Article  PubMed  CAS  Google Scholar 

  • Harro J, Tõnissaar M, Eller M, Kask A, Oreland L (2001) Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat: effects on behavior and monoamine neurochemistry. Brain Res 899:227–239

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K, Shimizu E, Iyo M (2004) Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev 45:104–114

    Article  CAS  PubMed  Google Scholar 

  • Hu S, Peterson PK, Chao CC (1997) Cytokine-mediated neuronal apoptosis. Neurochem Int 30:427–431

    Article  CAS  PubMed  Google Scholar 

  • Jackson JC, Hart RP, Gordon SM, Shintani A, Truman B, May L, Ely EW (2003) Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 31:1226–1234

    Article  PubMed  Google Scholar 

  • Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109:143–148

    Article  CAS  PubMed  Google Scholar 

  • Katz RJ, Roth KA, Carroll BJ (1981) Animal models and human depressive disorders. Neurosci Biobehav Rev 5:231–246

    Article  CAS  PubMed  Google Scholar 

  • Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8–19

    CAS  PubMed  Google Scholar 

  • Korte SM, Koolhaas JM, Wingfield JC, McEwen BS (2005) The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci Biobehav Rev 29:3–38

    Article  PubMed  Google Scholar 

  • Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902

    Article  CAS  PubMed  Google Scholar 

  • Lang UE, Hellweg R, Gallinat J (2004) BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 29:795–798

    Article  CAS  PubMed  Google Scholar 

  • Lee BH, Kim H, Park SH, Kim YK (2007) Decreased plasma BDNF level in depressive patients. J Affect Disord 101:239–244

    Article  CAS  PubMed  Google Scholar 

  • Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317

    Article  CAS  PubMed  Google Scholar 

  • Lucca G, Comim CM, Valvassori SS, Pereira JG, Stertz L, Gavioli EC, Kapczinski F, Quevedo J (2008) Chronic mild stress paradigm reduces sweet food intake in rats without affecting brain derived neurotrophic factor protein levels. Curr Neurovasc Res 5:207–213

    Article  CAS  PubMed  Google Scholar 

  • Mason BL, Pariante CM (2006) The effects of antidepressants on the hypothalamic–pituitary–adrenal axis. Drug News Perspect 19:603–608

    Article  CAS  PubMed  Google Scholar 

  • Maxime V, Siami S, Annane D (2007) Metabolism modulators in sepsis: the abnormal pituitary response. Crit Care Med 35:596–601

    Article  CAS  Google Scholar 

  • McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87:873–904

    Article  PubMed  Google Scholar 

  • Mesotten D, Vanhorebeek I, Van den Berghe G (2008) The altered adrenal axis and treatment with glucocorticoids during critical illness. Nat Clin Pract Endocrinol Metab 4:496–505

    Article  CAS  PubMed  Google Scholar 

  • Naert G, Ixart G, Tapia-Arancibia L, Givalois L (2006) Continuous i.c.v. infusion of brain-derived neurotrophic factor modifies hypothalamic–pituitary–adrenal axis activity, locomotor activity and body temperature rhythms in adult male rats. Neuroscience 139:779–789

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ, Gould E, Manji H, Buncan M, Duman RS, Greshenfeld HK, Hen R, Koester S, Lederhendler I, Meaney M, Robbins T, Winsky L, Zalcman S (2002) Preclinical model: status of basic research in depression. Biol Psychiatry 52:503–528

    Article  PubMed  Google Scholar 

  • Porter JC, Sisom JF, Arita J, Reymond MJ (1983) The hypothalamic-hypophysial vasculature and its relationship to secretory cells of the hypothalamus and pituitary gland. Vitam Horm 40:145–174

    Article  CAS  PubMed  Google Scholar 

  • Rage F, Givalois L, Marmigère F, Tapia-Arancibia L, Arancibia S (2002) Immobilization stress rapidly modulates BDNF mRNA expression in the hypothalamus of adult male rats. Neuroscience 112:309–318

    Article  CAS  PubMed  Google Scholar 

  • Rettori V, Dees WL, Hiney JK, Lyson K, McCann SM (1994) An interleukin-1alpha-like neuronal system in the preoptic-hypothalamic region and its induction by bacterial lipopolysaccharide in concentrations which alter pituitary hormone release. Neuroimmunomodulation 1:251–258

    Article  CAS  PubMed  Google Scholar 

  • Rietschel ET, Brade H, Holst O, Brade L, Müller-Loennies S, Mamat U, Zähringer U, Beckmann F, Seydel U, Brandenburg K, Ulmer AJ, Mattern T, Heine H, Schletter J, Loppnow H, Schönbeck U, Flad HD, Hauschildt S, Schade UF, Di Padova F, Kusumoto S, Schumann RR (1996) Bacterial endotoxin: chemical constitution, biological recognition, host response, and immunological detoxification. Curr Top Microbiol Immunol 216:39–81

    CAS  PubMed  Google Scholar 

  • Ritter C, Andrades M, Frota Júnior ML, Bonatto F, Pinho RA, Polydoro M, Klamt F, Pinheiro CT, Menna-Barreto SS, Moreira JC, Dal-Pizzol F (2003) Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation. Intensive Care Med 29:1782–1789

    Article  PubMed  Google Scholar 

  • Sanders VM (2006) Interdisciplinary research: noradrenergic regulation of adaptive immunity. Brain Behav Immunol 20:1–8

    Article  CAS  Google Scholar 

  • Schüle C, Baghai TC, Eser D, Zwanzger P, Jordan M, Buechs R, Rupprecht R (2006) Time course of hypothalamic-pituitary-adrenocortical axis activity during treatment with reboxetine and mirtazapine in depressed patients. Psychopharmacology (Berl) 186:601–611

    Article  CAS  Google Scholar 

  • Scragg P, Jones A, Fauvel N (2001) Psychological problems following ICU treatment. Anaesthesia 56:9–14

    Article  CAS  PubMed  Google Scholar 

  • Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, Heneka MT (2007) Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 204:733–740

    Article  PubMed  Google Scholar 

  • Sprung CL, Peduzzi PN, Shatney CH, Schein RM, Wilson MF, Sheagren JN, Hinshaw LB (1990) Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med 18:801–806

    Article  CAS  PubMed  Google Scholar 

  • Streck EL, Comim CM, Barichello T, Quevedo J (2008) The septic brain. Neurochem Res 33:2171–2177

    Article  CAS  PubMed  Google Scholar 

  • Strekalova T, Spanagel R, Dologov O, Bartsch D (2005) Stress-induced hyperlocomotion as a confounding factor in anxiety and depression models in mice. Behav Pharmacol 16:180–189

    Article  Google Scholar 

  • Tapia-Arancibia L, Rage F, Givalois L, Arancibia S (2004) Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol 25:77–107

    Article  CAS  PubMed  Google Scholar 

  • Tuon L, Comim CM, Antunes MM, Constantino LS, Machado RA, Izquierdo I, Quevedo J, Dal-Pizzol F (2007) Imipramine reverses the depressive symptoms in sepsis survivor rats. Intensive Care Med 33:2165–2167

    Article  CAS  PubMed  Google Scholar 

  • Tuon L, Comim CM, Petronilho F, Barichello T, Izquierdo I, Quevedo J, Dal-Pizzol F (2008) Time-dependent behavioral recovery after sepsis in rats. Intensive Care Med 34:1724–1731

    Article  CAS  PubMed  Google Scholar 

  • Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93:358–364

    Article  CAS  Google Scholar 

  • Willner P, Benton D, Brown E, Cheeta S, Davies G, Morgan J, Morgan M (1998) “Depression” increases “craving” for sweet rewards in animal and human models of depression and craving. Psychopharmacology (Berl) 136:272–283

    Article  CAS  Google Scholar 

  • Wrona D (2006) Neuronal-immune interactions: an integrative view of the bi-directional relationship between the brain and immune systems. J Neuroimmunol 172:38–58

    Article  CAS  PubMed  Google Scholar 

  • Young GB, Bolton CF, Austin TW, Archibald YM, Gonder J, Wells GA (1990) The encephalopathy associated with septic illness. Clin Invest Med 13:297–304

    CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by grants from CNPq (FK, TB, JQ, and FD-P), FAPESC (JQ and FD-P), Instituto Cérebro e Mente (TB, JQ, and FD-P), and UNESC (TB, JQ, and FD-P). FK, JQ, and FD-P are CNPq Research Fellows. FP is holder of a CAPES studentship, CMC is holder of a CNPq Studentship, and LSC is holder of a FAPESC studentship.

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Correspondence to João Quevedo.

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Comim, C.M., Cassol-Jr, O.J., Constantino, L.C. et al. Depressive-Like Parameters in Sepsis Survivor Rats. Neurotox Res 17, 279–286 (2010). https://doi.org/10.1007/s12640-009-9101-6

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  • DOI: https://doi.org/10.1007/s12640-009-9101-6

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