Skip to main content

Advertisement

SpringerLink
Log in

Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Sepsis is an organ dysfunction caused by an uncontrolled inflammatory response from the host to an infection. Sepsis is the main cause of morbidity and mortality in intensive care units (ICU) worldwide. One of the first organs to suffer from injuries resulting from sepsis is the brain. The central nervous system (CNS) is particularly vulnerable to damage, mediated by inflammatory and oxidative processes, which can cause the sepsis-associated encephalopathy (SAE), being reported in up to 70% of septic patients. This review aims to bring a summary of the main pathophysiological changes and dysfunctions in SAE, and the main focuses of current experimental studies for new treatments and therapies. The pathophysiology of SAE is complex and multifactorial, combining intertwined processes, and is promoted by countless alterations and dysfunctions resulting from sepsis, such as inflammation, neuroinflammation, oxidative stress, reduced brain metabolism, and injuries to the integrity of the blood-brain barrier (BBB). The treatment is limited once its cause is not completely understood. The patient’s sedation is far to provide an adequate treatment to this complex condition. Studies and experimental advances are important for a better understanding of its pathophysiology and for the development of new treatments, medicines, and therapies for the treatment of SAE and to reduce its effects during and after sepsis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

Not applicable.

Abbreviations

SAE:

Sepsis-associated encephalopathy

ICU:

Intensive care units

CNS:

Central nervous system

BBB:

Blood-brain barrier

TNF-α:

Necrosis factor alpha

IL:

Interleukins

CSF:

Cerebrospinal fluid

ROS:

Reactive oxygen species

NO:

Nitric oxide

RNS:

Reactive nitrogen species

H2O2 :

Hydrogen peroxide

O2 . :

Superoxide

.OH:

Hydroxyl

NO2 . :

Nitrogen dioxide

ATP:

Adenosine triphosphate

CLP:

Cecal ligation puncture procedure

FBP:

Fructose-1,6-bisphosphate

18F-FDG:

18F-fluoro-2-deoxy-d-glucose

GSDMD:

Gasdermin-D protein

CAT:

Catalase

GPx:

Glutathione peroxidase

KYN:

Kynurenine

SOD:

Superoxide dismutase

EE:

Ecballium elaterium

FBP:

Fructose-1,6-bisphosphate

Ngb:

Neuroglobin

FO:

Fish oil

IVIg:

Immunoglobulin

References

  1. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS et al (2016) Developing a newdefinition and assessing newclinical criteria for Septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA - J Am Med Assoc 315(8):775–787

    Article  CAS  Google Scholar 

  2. Gotts JE, Matthay MA (2016) Sepsis: pathophysiology and clinical management. BMJ 353:1–20

    Google Scholar 

  3. Delano MJ, Ward PA (2016) Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 126(1):23–31

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schulte W, Bernhagen J, Bucala R (2013) Cytokines in sepsis: potent immunoregulators and potential therapeutic targets - an updated view. Mediators Inflamm 2013.

  5. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39(2):165–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS et al (2016) Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA - J Am Med Assoc 315(8):775–787

    Article  CAS  Google Scholar 

  7. Cossart YE (2014) The rise and fall of infectious diseases: Australian perspectives, 1914-2014. Med J Aust 201(1 Suppl):11–14

    Google Scholar 

  8. Nedeva C, Menassa J, Puthalakath H (2019) Sepsis: inflammation is a necessary evil. Front Cell Dev Biol 7(JUN):1–12.

  9. Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P et al (2016) Assessment of global incidence and mortality of hospital-treated sepsis current estimates and limitations. Am J Respir Crit Care Med 193(3):259–272

    Article  CAS  PubMed  Google Scholar 

  10. Wang TL (2014) Prolonged neuroinflammation after lipopolysaccharide exposure in aged rats. PLoS One 9(8)

  11. Michelon C, Michels M, Abatti M, Vieira A, Borges H, Dominguini D et al (2020) The role of secretase pathway in long-term brain inflammation and cognitive impairment in an animal model of severe sepsis. Mol Neurobiol 57(2):1159–1169

    Article  CAS  PubMed  Google Scholar 

  12. Sankowski R, Mader S, Valdés-Ferrer SI (2015) Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci 9(FEB):1–20.

  13. Widmann CN, Heneka MT (2014) Long-term cerebral consequences of sepsis. Lancet Neurol 13(6):630–636

    Article  PubMed  Google Scholar 

  14. Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D (2013) Understanding brain dysfunction in sepsis. Ann Intensive Care 3(Figure 1):15.

  15. Kozlov AV, Bahrami S, Redl H, Szabo C (2017) Alterations in nitric oxide homeostasis during traumatic brain injury. Biochim Biophys Acta - Mol Basis Dis 1863(10):2627–2632

    Article  CAS  PubMed  Google Scholar 

  16. Robba C, Crippa IA, Taccone FS (2018) Septic encephalopathy. Curr Neurol Neurosci Rep 18(82)

  17. Taccone FS, Scolletta S, Franchi F, Donadello K, Oddo M (2013) Brain perfusion in sepsis. Curr Vasc Pharm 11(2):170–186

    CAS  Google Scholar 

  18. Young GB (2013) Encephalopathy of infection and systemic inflammation. J Clin Neurophysiol 30(5):454–461

    Article  PubMed  Google Scholar 

  19. Andonegui G, Zelinski EL, Schubert CL, Knight D, Craig LA, Winston BW et al (2018) Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment. JCI insight 3(9):1–20

    Article  Google Scholar 

  20. Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T (2016) Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med 37(2):333–345

    Article  PubMed  Google Scholar 

  21. Adam N, Kandelman S, Mantz J (2013) Sepsis-induced brain dysfunction. Expert Rev Anti Infect Ther 11(2):211–221

    Article  CAS  PubMed  Google Scholar 

  22. Tian M, Qingzhen L, Zhiyang Y, Chunlong C, Jiao D, Zhang L et al (2019) Attractylone attenuates sepsis-associated encephalopathy and cognitive dysfunction by inhibiting microglial activation and neuroinflammation. J Cell Biochem 120(5):7101–7108

    Article  Google Scholar 

  23. Michels M, Ávila P, Pescador B, Vieira A, Abatti M, Cucker L et al (2019) Microglial cells depletion increases inflammation and modifies microglial phenotypes in an animal model of severe sepsis. Mol Neurobiol 56(11):7296–7304

    Article  CAS  PubMed  Google Scholar 

  24. Shulyatnikova T, Verkhratsky A (2019) Astroglia in sepsis associated encephalopathy. Neurochem Res 45(1):83–99

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hoogland ICM, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D (2015) Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 12(1):1–13

    Article  CAS  Google Scholar 

  26. Lemstra AW, Cm J, Hoozemans JJM, Van Haastert ES, Rozemuller AJM, Eikelenboom P et al (2007) Microglia activation in sepsis: a case-control study. J Neuroinflammation 15(4):1–8

    Google Scholar 

  27. Danielski LG, Giustina A Della, Goldim MP, Florentino D, Mathias K, Garbossa L, et al. (2018) Vitamin B6 reduces neurochemical and long-term cognitive alterations after polymicrobial sepsis: involvement of the kynurenine pathway modulation. Mol Neurobiol 55(6):5255–5268

    Article  CAS  PubMed  Google Scholar 

  28. Bedirli N, Bagriacik EU, Yilmaz G, Ozkose Z, Kavutçu M, Cavunt Bayraktar A et al (2018) Sevoflurane exerts brain-protective effects against sepsis-associated encephalopathy and memory impairment through caspase 3/9 and Bax/Bcl signaling pathway in a rat model of sepsis. J Int Med Res 46(7):2828–2842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Danielski LG, Giustina A Della, Badawy M, Barichello T, Quevedo J, Dal-Pizzol F, et al. (2018) Brain barrier breakdown as a cause and consequence of neuroinflammation in sepsis. Mol Neurobiol 55(2):1045–1053

    Article  CAS  PubMed  Google Scholar 

  30. Nwafor DC, Brichacek AL, Mohammad AS, Griffith J, Lucke-Wold BP, Benkovic SA et al (2019) Targeting the blood-brain barrier to prevent sepsis-associated cognitive impairment. J Cent Nerv Syst Dis 11:117957351984065

    Article  Google Scholar 

  31. Bookheimer SY, Strojwas MH et al (2000) Patterns of brain activation in people at risk for Alzheimer’s disease. N Eng J Med 343(7):450–456

    Article  CAS  Google Scholar 

  32. Reiman EM, Caselli RJ, Chen K, Alexander GE, Bandy D, Frost J (2001) Declining brain activity in cognitively normal apolipoprotein epsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease. Proc Natl Acad Sci USA 98(6)

  33. Cunnane S, Ph D, Nugent S, Sc B, Roy M, Sc M, et al. (2011) Brain fuel metabolism , aging , and Alzheimer’s disease. Nutrition 27(1):3–20.

  34. Catarina A V, Luft C, Greggio S, Venturin GT, Ferreira F, Marques EP, et al. (2018) Fructose-1,6-bisphosphate preserves glucose metabolism integrity and reduces reactive oxygen species in the brain during experimental sepsis. Brain Res 1698:54–61.

  35. Dantzer R, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Garcia J, Kimeldorf DJ, Koelling RA (1955) Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 122:157–158

    Article  CAS  PubMed  Google Scholar 

  37. Gamache FW Jr DT (1982) Alterations in neurological function in head-injured patients experiencing major episodes of sepsis. Neurosurgery 10(2):468–472.

  38. Calsavara AJC, Nobre V, Barichello T, Teixeira AL (2018) Post-sepsis cognitive impairment and associated risk factors: a systematic review. Aust Crit Care 31(4):242–253

    Article  PubMed  Google Scholar 

  39. Ebersoldt M, Sharshar T, Annane D (2007) Sepsis-associated delirium. Intensive Care Med 33(6):941–950

    Article  PubMed  Google Scholar 

  40. Leon A, Lepousé C, Floch T, Graftieaux J (2006) Agression cérébrale au cours du sepsis sévère Brain injury during severe sepsis. Ann Fr Anesth Reanim 25(8):863–867

    Article  CAS  PubMed  Google Scholar 

  41. Dittus RS, Thomason JWW, Jackson JC, Shintani ÃAK, Ely EW, Mph à (2006) Delirium and its motoric subtypes: a study of 614 critically ill patients. J Am Geriatr Soc 54(3):479–484.

  42. Barichello T, Sayana P, Giridharan VV, Arumanayagam AS, Narendran B, Giustina A Della, et al. (2019) Long-term cognitive outcomes after sepsis: a translational systematic review. Mol Neurobiol 56(1):186–251

    Article  CAS  PubMed  Google Scholar 

  43. Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, et al. (2013) Persistent cognitive impairment , hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 84(1):62–69.

  44. Li W, Wang Y, Wang X, He Z, Liu F, Zhi W et al (2016) Esculin attenuates endotoxin shock induced by lipopolysaccharide in mouse and NO production in vitro through inhibition of NF-κB activation. Eur J Pharmacol 791(76):726–734

    Article  CAS  PubMed  Google Scholar 

  45. Qin X, Jiang X, Jiang X, Wang Y, Miao Z, He W (2016) Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge. Sci Rep :1–13.

  46. He H, Geng T, Chen P, Wang M, Hu J, Kang L et al (2016) OPEN NK cells promote neutrophil recruitment in the brain during sepsis-induced neuroinflammation. Sci Rep 6:1–14

    Google Scholar 

  47. Sharshar T, Gray F, Lorin G, Grandmaison D, Hopkinson NS, Ross E et al (2003) Mechanisms of disease Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362(9398):1799–1805

    Article  CAS  PubMed  Google Scholar 

  48. Alexander JJ, Jacob A et al (2008) TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. Neurochem int 52(3):447–456

    Article  CAS  PubMed  Google Scholar 

  49. Rorato R, Menezes AM, Giusti-paiva A, De Castro M (2009) Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats. Exp Physiol 94(3):371–379

    Article  CAS  PubMed  Google Scholar 

  50. Rump K, Adamzik M (2018) Function of aquaporins in sepsis: a systematic review. Cell Biosci 8:1–7

    Article  Google Scholar 

  51. Takatani Y, Ono K (2018) Inducible nitric oxide synthase during the late phase of sepsis is associated with hypothermia and immune cell migration. Lab Investig 98(5):629–639

    Article  CAS  PubMed  Google Scholar 

  52. Cunningham C, Maclullich AMJ (2013) At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response. Brain Behav Immun 28:1–13

    Article  PubMed  Google Scholar 

  53. Westhoff D, Engelen-Lee JY, Hoogland ICM, Aronica EMA, Van Westerloo DJ, Van De Beek D et al (2019) Systemic infection and microglia activation: a prospective postmortem study in sepsis patients. Immun Ageing 16(1):1–10

    Article  CAS  Google Scholar 

  54. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97(6):1634–1658

    Article  CAS  PubMed  Google Scholar 

  55. Brookes PS, Bolan JP, Y SJRH (1999) The assumption that nitric oxide inhibits mitochondrial ATP synthesis is correct. FEBS Lett 446(2–3):261–263.

  56. Berg RMG, Møller K, Bailey DM (2011) Neuro-oxidative-nitrosative stress in sepsis. J Cereb Blood Flow Metab 31(7):1532–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cassina A, Radi R (1996) Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 328(2):309–316

    Article  CAS  PubMed  Google Scholar 

  58. Tang G, Yang H, Chen J, Shi M, Ge L (2017) Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget 8(58):97977–97989.

  59. Zhu S, Huang W, Huang L, Han Y, Han Q (2016) Huperzine A protects sepsis associated encephalopathy by promoting the deficient cholinergic nervous function. Neurosci Lett 631:70–78

    Article  CAS  PubMed  Google Scholar 

  60. Semmler A, Okulla T, Sastre M, Dumitrescu-ozimek L, Heneka MT (2005) Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 30:144–157

    Article  CAS  PubMed  Google Scholar 

  61. Brain T The expensive-tissue. 36(2).

  62. Tsacopoulos M, Magistretti PJ (1996) Metabolic coupling between glia and neurons. J Neurosci. 16(3):877–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shulman RG, Hyder F, Rothman DL (2001) Cerebral energetics and the glycogen shunt: neurochemical basis of functional imaging. Proc Natl Acad Sci USA 98(11):6417–6422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gofton TE, Young GB (2012) Sepsis-associated encephalopathy. Nat Rev Neurol 8(October):557–566

    Article  CAS  PubMed  Google Scholar 

  65. Oddo M, Taccone FS (2015) How to monitor the brain in septic patients? Minerva Anestesiol 81(7):776–788

    CAS  PubMed  Google Scholar 

  66. Taccone FS, Castanares-Zapater, et al. (2010) Cerebral autoregulation is influenced by carbon dioxide levels in patients with septic shock. Neurocrit Care. 12(1):35–42

    Article  CAS  PubMed  Google Scholar 

  67. Semmler A, Hermann S (2008) Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 5:38

    Article  PubMed  PubMed Central  Google Scholar 

  68. Everson-Rose SA, Ryan JP (2015) Diabetes, obesity, and the brain: new developments in biobehavioral medicine. Psychosom Med 77(6):612–615

    Article  PubMed  PubMed Central  Google Scholar 

  69. Lin A-L, Parikh I, Hoffman JD, Ma D (2017) Neuroimaging biomarkers of caloric restriction on brain metabolic and vascular functions. Curr Nutr Rep 6(1):41–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bangen KJ, Beiser A, Delano-Wood L, Nation DA, Lamar M, Libon DJ et al (2013) APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline. J Stroke Cerebrovasc Dis 22(8):1361–1369

    Article  PubMed  Google Scholar 

  71. Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S et al (2012) Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition 27(1):3–20

    Article  Google Scholar 

  72. Keaney J, Campbell M (2015) The dynamic blood–brain barrier. FEBS J 282(21):4067–4079.

  73. Engelhardt B, Sorokin L (2009) The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31(4):497–511.

  74. Weighardt H, Holzmann B (2008) Role of Toll-like receptor responses for sepsis pathogenesis. Immunobiology 212(9–10):715–722

    Article  Google Scholar 

  75. Janeway CA, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20(2):197–216

    Article  CAS  PubMed  Google Scholar 

  76. Junior CAJ (2001) How the immune system protects the host from infection. Microbes Infect 3(13):1167–1171

    Article  Google Scholar 

  77. Chapouly C, Argaw AT, Horng S, Castro K, Zhang J, Asp L, et al. (2015) Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions. Brain 138(6):1548–1567.

  78. Vincent VAM, Tilders FJH, Dam AVAN (1997) Inhibition of endotoxin-induced nitric oxide synthase production in microglial cells by the presence of astroglial cells: a role for transforming growth factor. Glia 19(3):190–198.

  79. Lee SC (1993) Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol 150(7):2659–2667

    Article  CAS  PubMed  Google Scholar 

  80. Geissmann F, Markus G, Manz SJ, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327(5966):656–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Opal SM, Ellis JL, Suri V, Freudenberg JM, Vlasuk GP, Li Y et al (2016) Pharmacological SIRT1 activation improves mortality and markedly alters transcriptional profiles that accompany experimental sepsis. Shock 45(4):411–418

    Article  CAS  PubMed  Google Scholar 

  82. Zhao L, An R, Yang Y, Yang X, Liu H, Yue L et al (2015) Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating in fl ammation, apoptosis, and oxidative stress: the role of SIRT1 signaling. J Pineal Res 59(2):230–239

    Article  CAS  PubMed  Google Scholar 

  83. Hernández-Jiménez M, Hurtado O, Cuartero MI, Ballesteros I, Moraga A, Pradillo JM et al (2013) Silent information regulator 1 protects the brain against cerebral ischemic damage. Stroke 44(8):2333–2337

    Article  PubMed  Google Scholar 

  84. Bai XZ, He T, Gao JX, Liu Y, Liu JQ, Han SC et al (2016) Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1. Sci Rep 6(August):1–13

    Google Scholar 

  85. Zhu Y, Wang K, Ma Z, Liu D, Yang Y, Sun M et al (2019) SIRT1 activation by butein attenuates sepsis-induced brain injury in mice subjected to cecal ligation and puncture via alleviating inflammatory and oxidative stress. Toxicol Appl Pharmacol 363:34–46

    Article  CAS  PubMed  Google Scholar 

  86. Lee D, Jeong G (2016) Butein provides neuroprotective and anti-neuroin fl ammatory effects through expression by activating the PI3K/Akt pathway Tables of Links. Br J Pharmacol 173(19):2894–2909.

  87. Padmavathi G, Kishor N, Bordoloi D, Arfuso F, Mishra S, Sethi G, et al. (2017) Phytomedicine butein in health and disease: a comprehensive review. Phytomedicine 25:118–127.

  88. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H et al (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 562:660–665

    Article  Google Scholar 

  89. Kayagaki N, Stowe IB, Lee BL, Rourke KO, Anderson K, Warming S et al (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671

    Article  CAS  PubMed  Google Scholar 

  90. Khan M, Shah SA, Kim MO (2018) 17β-estradiol via SIRT1/acetyl-p53/NF-kB signaling pathway rescued postnatal rat brain against acute ethanol intoxication. Mol Neurobiol 55(4):3067–3078

    Article  CAS  PubMed  Google Scholar 

  91. Kou D-Q, Jiang Y-L, Qin J-H, Huang Y-H (2017) Magnolol attenuates the inflammation and apoptosis through the activation of SIRT1 in experimental stroke rats. Pharmacol Rep 69(4):642–647

    Article  CAS  PubMed  Google Scholar 

  92. Al. P. BA. Z et (2016) Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high fat diet. Physiol Behav 176(1):139–148.

  93. Xu X e., Liu L, Wang Y chang, Wang C tao, Zheng Q, Liu Q xin, et al. (2019) Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis. Brain Behav Immun 80(January):859–870

    Google Scholar 

  94. Wang P, Hu Y, Yao D, Li Y (2018) Omi/HtrA2 regulates a mitochondria-dependent apoptotic pathway in a murine model of septic encephalopathy. Cell Physiol Biochem 49(6):2163–2173

    Article  CAS  PubMed  Google Scholar 

  95. Lacroix-desmazes S, Kazatchkine MD, Kaveri SV (2005) Intravenous immunoglobulin in neurological disorders: a mechanistic perspective. J Neurol 252:1–6

    Article  Google Scholar 

  96. Esen F, Ozcan PE, Tuzun E, Boone MD (2018) Mechanisms of action of intravenous immunoglobulin in septic encephalopathy. Rev Neurosci 29(4):417–423

    Article  CAS  PubMed  Google Scholar 

  97. Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K–Akt signaling pathway. Curr Opin Neurobiol 11(3):297–305.

  98. Burmester T, Weich B, Reinhardt S (2000) A vertebrate globin expressed in the brain. 407(September):1998–2001.

  99. Raida Z, Hundahl CA, Nyengaard JR, Hay-schmidt A (2013) Neuroglobin over expressing mice: expression pattern and effect on brain ischemic infarct size. PLoS One 8(10):e 76565.

  100. Zhang LN, Ai YH, Gong H, Guo QL, Huang L, Liu ZY YB (2014) Expression and role of neuroglobin in rats with sepsis-associated encephalopathy*. Crit Care Med 42(1):e 12-21.

  101. Deng S, Ai Y, Gong H, Chen C, Peng Q, Huang L et al (2017) Neuroglobin protects rats from sepsis-associated encephalopathy via a PI3K/Akt/Bax-dependent mechanism. J Mol Neurosci 63(1):1–8

    Article  CAS  PubMed  Google Scholar 

  102. Campbell BM, Charych E, Lee AW, Möller T, Dantzer R (2014) Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci 8(February):1–22

    Google Scholar 

  103. Maddison DC, Giorgini F (2015) The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol 40:134–141

    Article  CAS  PubMed  Google Scholar 

  104. Bordignon Nunes F, Simões Pires MG, Alves Filho JCF, Wächter PH, De Oliveira JR (2002) Physiopathological studies in septic rats and the use of fructose 1,6-bisphosphate as cellular protection. Crit Care Med 30(9):2069–2074

    Article  Google Scholar 

  105. Pedrazza L, Lunardelli A, Luft C, Cruz CU, De Mesquita FC, Bitencourt S et al (2014) Mesenchymal stem cells decrease splenocytes apoptosis in a sepsis experimental model. Inflamm Res 63(9):719–728

    Article  CAS  PubMed  Google Scholar 

  106. Moataz E, El B, Chalupov M, Pra G, Suchý P (2015) Hepatoprotective and proapoptotic effect of Ecballium elaterium on CCl4-induced hepatotoxicity in rats. Asian Pac J Trop Med 8(7):526–531

    Article  Google Scholar 

  107. Uslu C, Karasen RM, Sahin F (2006) Effect of aqueous extracts of Ecballium elaterium rich, in the rabbit model of rhinosinusitis. Int J Pediatr Otorhinolaryngol 70(3):515–518

    Article  PubMed  Google Scholar 

  108. Arslan D, Ekinci A, Arici A, Bozdemir E, Akil E, Ozdemir HH (2017) Effects of Ecballium elaterium on brain in a rat model of sepsis-associated encephalopathy. Libyan J Med 12(1)

  109. Sc DM, Della A, Ph G, Pereira M, Ph G, Eduarda M et al (2020) Fish oil À rich lipid emulsion modulates neuroin fl ammation and prevents long-term cognitive dysfunction after sepsis. Nutrition 70:1–9

    Google Scholar 

Download references

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—finance code 001.

Author information

Authors and Affiliations

  1. Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA, Porto Alegre, RS, 90050-170, Brazil

    Anderson Velasque Catarina, Gisele Branchini, Lais Bettoni & Fernanda Bordignon Nunes

  2. Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Porto Alegre, Brazil

    Jarbas Rodrigues De Oliveira & Fernanda Bordignon Nunes

Authors
  1. Anderson Velasque Catarina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gisele Branchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lais Bettoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jarbas Rodrigues De Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fernanda Bordignon Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have been involved in drafting the manuscript or revising it critically for important intellectual content.

Corresponding author

Correspondence to Anderson Velasque Catarina.

Ethics declarations

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Consent to Participate

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Catarina, A.V., Branchini, G., Bettoni, L. et al. Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies. Mol Neurobiol 58, 2770–2779 (2021). https://doi.org/10.1007/s12035-021-02303-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02303-2

Keywords

Search

Navigation