Neurochemical Research

, Volume 33, Issue 11, pp 2171–2177

The Septic Brain

  • Emilio L. Streck
  • Clarissa M. Comim
  • Tatiana Barichello
  • João Quevedo
Overview

Abstract

Sepsis is a major disease entity with important clinical implications. Sepsis-induced multiple organ failure is associated with a high mortality rate in humans and is clinically characterized by pulmonary, cardiovascular, renal and gastrointestinal dysfunction. Recently, several studies have demonstrated that sepsis survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. However, the pathogenesis and natural history of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. This review discusses the clinical presentation and underlying pathophysiology of the encephalopathy and cognitive impairment associated with sepsis.

Keywords

Sepsis Encephalopathy Cognitive impairment 

Abbreviations

5HT-1A

Serotonin receptor type 1A

ACTH

Adrenocorticotropic hormone

AMPc

Adenosine monophosphate cyclic

BBB

Blood–brain barrier

BDNF

Brain derived-neurotrofic factor

CLP

Cecal ligation and perforation

CNS

Central nervous system

DFX

Deferoxamine

CREB

cAMP response element-binding

ICU

Intensive care unit

GABAA

Gama-aminobutyric acid receptor type A

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

NAC

N-Acetylcysteine

NMDA

N-Methyl-d-aspartic acid

NSE

Neuron-specific enolase

PKA

Protein kinase A

PKC

Protein kinase C

mRNA

Messenger ribonucleic acid

SE

Septic encephalopathy

SIRS

Systemic inflammatory response syndrome

VAChT

Vesicle transporters of acetylcholine

References

  1. 1.
    Vandijck D, Decruyenaere JM, Blot SI (2006) The value of sepsis definitions in daily ICU-practice. Acta Clin Belg 6:220–226Google Scholar
  2. 2.
    Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–142PubMedGoogle Scholar
  3. 3.
    Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340:207–214PubMedGoogle Scholar
  4. 4.
    Bone RC, Grodzin CJ, Balk RA (1997) Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 112:235–243PubMedGoogle Scholar
  5. 5.
    Sands KE, Bates DW, Lanken PN et al (1997) Academic Medical Center Consortium Sepsis Project Working Group: epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 278:234–238PubMedGoogle Scholar
  6. 6.
    Brun-Buisson C (2000) The epidemiology of the systemic inflammatory response. Intensive Care Med 26:S64–S74PubMedGoogle Scholar
  7. 7.
    Friedman G, Silva E, Vincent JL (1998) Has the mortality of septic shock changed with time? Crit Care Med 26:2078–2086PubMedGoogle Scholar
  8. 8.
    Hotchkiss RS, Karl IK (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150PubMedGoogle Scholar
  9. 9.
    Tran DD, Groeneveld AB, Van Der Meulen J et al (1990) Age, chronic disease, sepsis, organ system failure, and mortality in a medical intensive care unit. Crit Care Med 18:474–479PubMedGoogle Scholar
  10. 10.
    O’Brien JM Jr, Ali NA, Abraham E (2005) Year in review in Critical Care, 2004: sepsis and multi-organ failure. Crit Care 9:409–413PubMedGoogle Scholar
  11. 11.
    Young GB, Bolton CF, Austin TW et al (1990) The encephalopathy associated with septic illness. Clin Invest Med 13:297–304PubMedGoogle Scholar
  12. 12.
    Sprung CL, Peduzzi PN, Shatney CH et al (1990) Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med 18:801–806PubMedGoogle Scholar
  13. 13.
    Bleck TP, Smith MC, Pierre-Louis SJ et al (1993) Neurologic complications of critical medical illnesses. Crit Care Med 21:98–103PubMedCrossRefGoogle Scholar
  14. 14.
    Papadopoulos MC, Davies DC, Moss RF et al (2000) Pathophysiology of septic encephalopathy: a review. Crit Care Med 28:3019–3024PubMedGoogle Scholar
  15. 15.
    Sharshar T, Annane D, de la Grandmaison GL et al (2004) The neuropathology of septic shock. Brain Pathol 14:21–33PubMedGoogle Scholar
  16. 16.
    Sharshar T, Gray F, de la Grandmaison GL et al (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362:1799–1805PubMedGoogle Scholar
  17. 17.
    Spyer KM (1989) Neural mechanisms involved in cardiovascular control during affective behaviour. Trends Neurosci 12:506–513PubMedGoogle Scholar
  18. 18.
    Saper CB, Breder CD (1994) The neurologic basis of fever. N Engl J Med 330:1880–1886PubMedGoogle Scholar
  19. 19.
    Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavorial homeostasis. JAMA 267:1244–1252PubMedGoogle Scholar
  20. 20.
    Chrousos GP (1995) The hypothalamic-pituitary-adrenal-axis and immune-mediated inflammation. N Engl J Med 332:1351–1362PubMedGoogle Scholar
  21. 21.
    Angus DC, Musthafa AA, Clermont G et al (2001) Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am J Respir Crit Care Med 163:1389–1394PubMedGoogle Scholar
  22. 22.
    Gordon SM, Jackson JC, Ely EW et al (2004) Clinical identification of cognitive impairment in ICU survivors: insights for intensivists. Intensive Care Med 30:1997–2008PubMedGoogle Scholar
  23. 23.
    Granja C, Dias C, Costa-Pereira A et al (2004) Quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness. Crit Care 8:91–98Google Scholar
  24. 24.
    Granja C, Lopes A, Moreira S et al (2005) JMIP Study Group: patients’ recollections of experiences in the intensive care unit may affect their quality of life. Crit Care 9:96–109Google Scholar
  25. 25.
    Heyland DK, Hopman W, Coo H et al (2000) Long-term health-related quality of life in survivors of sepsis. Short Form 36: a valid and reliable measure of health-related quality of life. Crit Care Med 28:3599–3605PubMedGoogle Scholar
  26. 26.
    Hopkins RO, Weaver LK, Pope D et al (1999) Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 160:50–56PubMedGoogle Scholar
  27. 27.
    Hopkins RO, Weaver LK, Collingridge D et al (2005) Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 171:340–347PubMedGoogle Scholar
  28. 28.
    Hough CL, Curtis JR (2005) Long-term sequelae of critical illness: memories and health-related quality of life. Crit Care 9:145–146PubMedGoogle Scholar
  29. 29.
    Jackson JC, Gordon SM, Ely EW et al (2004) Research issues in the evaluation of cognitive impairment in intensive care unit survivors. Intensive Care Med 30:2009–2016PubMedGoogle Scholar
  30. 30.
    Ritter C, Andrades ME, Reinke A et al (2004) Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis. Crit Care Med 32:342–349PubMedGoogle Scholar
  31. 31.
    De Souza LF, Ritter C, Gelain DP et al (2007) Mitochondrial superoxide production is related to the control of cytokine release from peritoneal macrophage after antioxidant treatment in septic rats. J Surg Res 141:252–256PubMedGoogle Scholar
  32. 32.
    Quevedo J, Vianna MRM, Roesler R et al (1999) Two time windows for anisomycin-induced amnesia for inhibitory avoidance training in rats: protection from amnesia by pretraining but not pre-exposure to the task apparatus. Learn Mem 6:600–607PubMedGoogle Scholar
  33. 33.
    Matthies H (1982) Plasticity in the nervous system: an approach to memory research. In: Ajmone-Marsan C, Matthies H (eds) Neuronal plasticity and memory formation. Raven Press, New York, pp 1–15Google Scholar
  34. 34.
    Matthies H (1989) In search of the cellular mechanisms of memory. Prog Neurobiol 32:277–349PubMedGoogle Scholar
  35. 35.
    Rose SPR (1995) Cell-adhesion molecules, glucocorticoids and long-term memory formation. Trends Neurosci 18:502–506PubMedGoogle Scholar
  36. 36.
    Frey U, Schollmeier K, Reymann KG et al (1995) Asymptotic hippocampal long-term potentiation in rats does not preclude additional potentiation at later phases. Neuroscience 67:799–807PubMedGoogle Scholar
  37. 37.
    Rose SPR (1995) Time-dependent biochemical and cellular processes in memory processes in memory formation. In: McGaugh JL, Bermúdez-Rattoni F, Prado-Alcalá RA (eds) Plasticity in the central nervous system: learning and memory. Erlbaum, Mahwah, pp 67–82Google Scholar
  38. 38.
    Rossato JI, Bevilaqua LR, Myskiw JC et al (2007) On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory. Learn Mem 14:36–46PubMedGoogle Scholar
  39. 39.
    Perrin G, Ferreira G, Meurisse M et al (2007) Social recognition memory requires protein synthesis after reactivation. Behav Neurosci 121:148–155PubMedGoogle Scholar
  40. 40.
    Alkon DL, Epstein H, Kuzirian A et al (2005) Protein synthesis required for long-term memory is induced by PKC activation on days before associate learning. Proc Natl Acad Sci 102:16432–16437PubMedGoogle Scholar
  41. 41.
    Quevedo J, Sant’Anna MK, Madruga M et al (2003) Differential effects of emotional arousal in short- and long-term memory in healthy adults. Neurobiol Learn Mem 79:132–135PubMedGoogle Scholar
  42. 42.
    McGaugh JL, Izquierdo I (2000) The contribution of pharmacology to research on the mechanisms of memory formation. Trends Pharmacol Sci 21:208–210PubMedGoogle Scholar
  43. 43.
    de Wied D (1964) Influence of anterior pituitary on avoidance learning and escape behavior. Am J Physiol 207:255–259Google Scholar
  44. 44.
    de Wied D (1993) From stress hormones to neuropeptides. In: Burbach JPH, De Wied D (eds) Brain functions of neuropeptides. Parthenon, CarnforthGoogle Scholar
  45. 45.
    Gold PE, van Buskirk R (1975) Facilitation of time-dependent memory processes whit posttrial epinephrine injections. Behav Biol 13:145–153PubMedGoogle Scholar
  46. 46.
    Gold PE, van Buskirk R (1976) Enhancement and impairment of memory processes whit posttrial injections of adrenocorticotrophic hormones. Behav Biol 16:387–400PubMedGoogle Scholar
  47. 47.
    McGaugh JL (1983) Hormonal influences on memory. Ann Rev Psychol 34:229–241Google Scholar
  48. 48.
    Bohus B (1994) Humoral modulation of learning and memory processes: physiological significance of brain and peripheral mechanisms. In: Delacour J (ed) The memory systems of the brain. World Scientific, SingaporeGoogle Scholar
  49. 49.
    Rose SPR (2000) God’s organism? The chick as a model system for memory studies. Learn Mem 7:1–17PubMedGoogle Scholar
  50. 50.
    Roozendaal B, McGaugh JL (1996) Amygdaloid nuclei lesions differentially affect glucocorticoid-induced memory enhancement in an inhibitory avoidance task. Neurobiol Learn Mem 65:1–8PubMedGoogle Scholar
  51. 51.
    McGaugh JL, Cahill L, Roozendaal B (1996) Involvement of the amygdala in memory storage: interaction with other brain systems. Proc Natl Acad Sci 26:13508–13514Google Scholar
  52. 52.
    Ferry B, Roozendaal B, McGaugh JL (1999) Role of norepinephrine in mediating stress hormone regulation of long-term storage: a critical involvement of the amygdala. Biol Psychiatry 46:1140–1152PubMedGoogle Scholar
  53. 53.
    Setlow B, Roozendaal B, McGaugh JL (2000) Involvement of a basolateral amygdala complex-nucleus accumbens pathway in glicocorticoid-induced modulation of memory consolidation. Eur J Neurosci 12:367–375PubMedGoogle Scholar
  54. 54.
    Izquierdo I (1989) Different forms of posttaining memory processing. Behav Neural Biol 51:171–202PubMedGoogle Scholar
  55. 55.
    Izquierdo I (1991) Opioids and memory. In: Stone TW (ed) Aspects of synaptic transmission. Taylor and Francis, LondonGoogle Scholar
  56. 56.
    Cahill L, McGaugh JL (1998) Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 11:294–299Google Scholar
  57. 57.
    McGaugh JL (2000) Memory: a century of consolidation. Science 287:248–251PubMedGoogle Scholar
  58. 58.
    Izquierdo I, Medina JH (1997) Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem 68:285–316PubMedGoogle Scholar
  59. 59.
    Izquierdo I, da-Cunha C, Rosat R et al (1992) Neurotransmitter receptors involved in memory processing by the amygdala, medial septum and hippocampus of rats. Behav Neural Biol 58:16–25PubMedGoogle Scholar
  60. 60.
    Brioni JD (1993) Role of GABA during the multiple consolidation of memory. Drug Develop Res 28:3–27Google Scholar
  61. 61.
    Izquierdo I, Quillfeldt JA, Zanatta MS et al (1997) Sequential involvement of hippocampus and amygdala, entorhinal cortex and parietal cortex in the formation and expression of memory for inhibitory avoidance in rats. Eur J Neurosci 9:786–793PubMedGoogle Scholar
  62. 62.
    Quevedo J, Moretto A, Colvero M et al (1997) The N-methyl-d-aspartate receptor blocker MK-801 prevents the facilitatory effects of naloxone and epinephrine on retention of inhibitory avoidance task in rats. Behav Pharmacol 8:471–474PubMedGoogle Scholar
  63. 63.
    Quevedo J, Vianna M, Zanatta MS et al (1997) Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory. Behav Pharmacol 8:713–717PubMedGoogle Scholar
  64. 64.
    Roesler R, Kuyven CR, Kruel AV et al (1998) Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats. Braz J Med Biol Res 3:1601–1604Google Scholar
  65. 65.
    Roesler R, Vianna M, Sant’Anna MK et al (1998) Intrahippocampal infusion of the NMDA receptor antagonist AP5 impairs retention of an inhibitory avoidance task: protection from impairment by pretraining or preexposure to the task apparatus. Neurobiol Learn Mem 69:87–91PubMedGoogle Scholar
  66. 66.
    Roesler R, Vianna MR, de-Paris F et al (1999) Memory-enhancing treatments do not reverse the impairment of inhibitory avoidance retention induced by NMDA receptor blockade. Neurobiol Learn Mem 72:252–258PubMedGoogle Scholar
  67. 67.
    Roesler R, Vianna MR, de-Paris F et al (2000) Infusions of AP5 into the basolateral amygdala impair the formation, but not the expression, of step-down inhibitory avoidance. Braz J Med Biol Res 33:829–834PubMedGoogle Scholar
  68. 68.
    Roesler R, Vianna MR, de-Paris F et al (2000) NMDA receptor antagonism in the basolateral amygdala blocks enhancement of inhibitory avoidance learning in previously trained rats. Behav Brain Res 112:99–105PubMedGoogle Scholar
  69. 69.
    Ardenghi P, Barros DM, Izquierdo LA et al (1997) Late and prolonged memory modulation in entorhinal and parietal cortex by drugs acting on the camp/protein kinase. A signaling pathway. Behav Pharmacol 8:745–751PubMedGoogle Scholar
  70. 70.
    Bevilaqua L, Ardenghi P, Schroder N et al (1997) Drugs that influence the cyclic adenosine monophosphate/protein kinase. A signaling pathway alter memory consolidation when given late after training into rat hippocampus but not amygdala. Behav Pharmacol 8:331–338PubMedGoogle Scholar
  71. 71.
    Walz R, Rockenbach IC, Amaral OB et al (1999) MAPK and memory. Trends Neurosci 22:495PubMedGoogle Scholar
  72. 72.
    Walz R, Roesler R, Quevedo J et al (1999) Dose-dependent impairment of inhibitory avoidance retention in rats by immediate posttraining infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures. Behav Brain Res 10:219–233Google Scholar
  73. 73.
    Walz R, Roesler R, Barros DM et al (1999) Effects of post-training infusions of a mitogen-activated protein kinase kinase inhibitor into the hippocampus or entorhiunal cortex on short- and long-term retention of inhibitory avoidance. Behav Pharmacol 10:723–730PubMedGoogle Scholar
  74. 74.
    Walz R, Roesler R, Quevedo J et al (2000) Time-dependent impairment of inhibitory avoidance retention in rats by posttraining infusion of a mitogen-activated protein kinase kinase inhibitor into cortical and limbic structures. Neurobiol Learn Mem 73:11–20PubMedGoogle Scholar
  75. 75.
    Squire LR, Zola-Morgan S (1991) The medial temporal lobe memory system. Science 20:1380–1386Google Scholar
  76. 76.
    Jorrard LD (1995) What does the hippocampus really do? Behav Brain Res 71:1–10Google Scholar
  77. 77.
    Gordon SM, Jackson JC (2004) Clinical identification of cognitive impairment in ICU survivors: insights for intensivists. Intensive Care Med 30:1997–2008PubMedGoogle Scholar
  78. 78.
    Semmler A, Okulla T, Sastre M et al (2005) Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 30:144–157PubMedGoogle Scholar
  79. 79.
    Rothenhausler HB, Ehrentraut S, Stoll C et al (2001) The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study. Gen Hosp Psychiatry 23:90–96PubMedGoogle Scholar
  80. 80.
    Jes C, Griffiths RD, Slater TC et al (2006) Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness. Intensive Care Med 32:923–926Google Scholar
  81. 81.
    Sukantarat KT, Burgess PW, Williamson RC et al (2005) Prolonged cognitive dysfunction in survivors of critical illness. Anaesthesia 60:847–853PubMedGoogle Scholar
  82. 82.
    Hopkins RO, Weaver LK, Chan KJ et al (2004) Quality of life, emotional, and cognitive function following acute respiratory distress syndrome. J Int Neuropsychol Soc 10:1005–1017PubMedGoogle Scholar
  83. 83.
    Barichello T, Martins MR, Reinke A et al (2005) Cognitive impairment in sepsis survivors from cecal ligation and perforation. Crit Care Med 33:221–223PubMedGoogle Scholar
  84. 84.
    Barichello T, Martins MR, Reinke A et al (2005) Long-term cognitive impairment in sepsis survivors. Crit Care Med 33:1671PubMedGoogle Scholar
  85. 85.
    Barichello T, Martins MR, Reinke A et al (2007) Behavioural deficits in CLP-induced sepsis survivor rats. Braz J Med Biol Res 40:831–837PubMedGoogle Scholar
  86. 86.
    Scragg P, Jones A, Fauvel N (2001) Psychological problems following ICU treatment. Anaesthesia 56:9–14PubMedGoogle Scholar
  87. 87.
    Skozol JW, Vender JS (2001) Vender anxiety, delirium, and pain in an intensive care unit. Crit Care Clin 17:821–842Google Scholar
  88. 88.
    Hart RP, Kwentus JA, Taylor JR et al (1997) Rate of forgetting in dementia and depression. J Consult Clin Psychol 55:101–105Google Scholar
  89. 89.
    Jones RD, Tranel D, Benton A et al (1992) Differentiating dementia from pseudo-dementia early in the clinical course: utility of neuropsychological tests. Neuropsychology 6:13–21Google Scholar
  90. 90.
    Nestler EJ, Barrot M, DiLeone RJ et al (2002) Neurobiology of depression. Neuron 28:13–25Google Scholar
  91. 91.
    Tuon L, Comim CM, Antunes MM et al (2007) Imipramine reverses the depressive symptoms in sepsis survivor rats. Intensive Care Med 33:2165–2167PubMedGoogle Scholar
  92. 92.
    Barichello T, Fortunato JJ, Vitali AM et al (2006) Oxidative variables in the brain after sepsis induced by cecal ligation and perforation. Crit Care Med 34:886–889PubMedGoogle Scholar
  93. 93.
    Barichello T, Machado RA, Constantino L et al (2007) Antioxidant treatment reverses late cognitive impairment in an animal model of sepsis. Crit Care Med 35:2186–2190PubMedGoogle Scholar
  94. 94.
    Semmler A, Frisch C, Debeir T et al (2007) Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 204:733–740PubMedGoogle Scholar
  95. 95.
    Heidbreder CA, Groenewegen HJ (2003) The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev 27:555–579PubMedGoogle Scholar
  96. 96.
    Mogensen J, Moustgaard A, Khan U et al (2005) Egocentric spatial orientation in a water maze by rats subjected to transaction of the fimbria-fornix and/or ablation of the prefrontal cortex. Brain Res Bull 65:41–58PubMedGoogle Scholar
  97. 97.
    Dixon CE, Kochanek PM, Yan HQ et al (1999) One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats. J Neurotrauma 16:109–122PubMedCrossRefGoogle Scholar
  98. 98.
    Gilmor ML, Nash N, Roghani RA et al (1996) Expression of the putative vesicular acetylcholine transporter in rat brain and localization in cholinergic synaptic vesicles. J Neurosci 16:2179–2190PubMedGoogle Scholar
  99. 99.
    Arvidsson U, Riedl M, Elde R et al (1997) Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J Comp Neurol 378:454–467PubMedGoogle Scholar
  100. 100.
    Mesulam MM, Mufson EJ, Wainer BH et al (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6). Neuroscience 10:1185–1201PubMedGoogle Scholar
  101. 101.
    Gage FH, Bjorklund B, Stenevi U (1983) Reinnervation of the partially deafferented hippocampus by compensatory collateral sprouting from spared cholinergic and noradrenergic afferents. Brain Res 268:27–37PubMedGoogle Scholar
  102. 102.
    Eckenstein FP, Baughman RW, Quinn J (1988) An anatomical study of cholinergic innervation in rat cerebral cortex. Neuroscience 25:457–474PubMedGoogle Scholar
  103. 103.
    Dantzer R, O’Connor JC, Freund GG et al (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56PubMedGoogle Scholar
  104. 104.
    De Bock F, Derijard B, Dornand J et al (1998) The neuronal death induced by endotoxic shock but not that induced by excitatory amino acids requires TNF-alpha. Eur J Neurosci 10:3107–3114PubMedGoogle Scholar
  105. 105.
    Sharshar T, Annane D, De la Grandmaison GL et al (2004) The neuropathology of septic shock. Brain Pathol 14:21–33PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Emilio L. Streck
    • 1
  • Clarissa M. Comim
    • 2
  • Tatiana Barichello
    • 1
  • João Quevedo
    • 2
  1. 1.Laboratório de Fisiopatologia Experimental, Programa de Pós-graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciumaBrazil
  2. 2.Laboratório de Neurociências, Programa de Pós-graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciumaBrazil

Personalised recommendations