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Pathogenesis of sepsis-associated encephalopathy: more than blood–brain barrier dysfunction

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Abstract

Sepsis-associated encephalopathy is a common neurological complication of sepsis and is responsible for higher mortality and poorer long-term outcomes in septic patients. Sepsis-associated encephalopathy symptoms can range from mild delirium to deep coma, which occurs in up to 70% of patients in intensive care units. The pathological changes in the brain associated with sepsis include cerebral ischaemia, cerebral haemorrhage, abscess and progressive multifocal necrotic leukoencephalopathy. Several mechanisms are involved in the pathogenesis of sepsis-associated encephalopathy, such as blood–brain barrier dysfunction, cerebral blood flow impairment, glial cell activation, leukocyte transmigration, and neurotransmitter disturbances. These events are interrelated and influence each other, therefore they do not act as independent factors. This review is focused on new evidence showing the pathological process of sepsis-associated encephalopathy.

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All authors declares that all data support their published claims and comply with field standards.

Abbreviations

SAE:

Sepsis-associated encephalopathy

CNS:

Cerebral blood flow

CSF:

Cerebrospinal fluid

BBB:

Blood–brain barrier

LPS:

Lipopolysaccharide

GABA:

Gamma-aminobutyric acid

AChE:

Acetylcholinesterase

5-HIIA:

5-Hydroxyindoleacetic acid

References

  1. Singer M, Deutschman CS, Seymour CW et al (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315(8):801–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fleischmann C, Scherag A, Adhikari NK 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 

  3. Schuler A, Wulf DA, Lu Y et al (2018) The impact of acute organ dysfunction on long-term survival in sepsis. Crit Care Med 46(6):843–849

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chung HY, Wickel J, Brunkhorst FM et al (2020) Sepsis-associated encephalopathy: from delirium to dementia? J Clin Med 9(3):703

    Article  PubMed Central  Google Scholar 

  5. Kikuchi DS, Campos ACP, Qu H et al (2019) Poldip2 mediates blood–brain barrier disruption in a model of sepsis-associated encephalopathy. J Neuroinflamm 16(1):241

    Article  CAS  Google Scholar 

  6. Kuperberg SJ, Wadgaonkar R (2017) Sepsis-associated encephalopathy: the blood–brain barrier and the sphingolipid rheostat. Front Immunol 8:597

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhao L, Wang Y, Ge Z et al (2021) Mechanical learning for prediction of sepsis-associated encephalopathy. Front Comput Neurosci 15:739265

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ai ML, Huang L, Feng Q et al (2019) The clinical significance of transcranial Doppler in early diagnosis of sepsis-associated encephalopathy. Zhonghua nei ke za zhi 58(11):814–818

    CAS  PubMed  Google Scholar 

  9. Shulyatnikova T, Verkhratsky A (2020) Astroglia in sepsis associated encephalopathy. Neurochem Res 45(1):83–99

    Article  CAS  PubMed  Google Scholar 

  10. Ren C, Yao RQ, Zhang H et al (2020) Sepsis-associated encephalopathy: a vicious cycle of immunosuppression. J Neuroinflamm 17(1):14

    Article  CAS  Google Scholar 

  11. Czempik PF, Pluta MP, Krzych LJ (2020) Sepsis-associated brain dysfunction: a review of current literature. Int J Environ Res Public Health 17(16):5852

    Article  CAS  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Jin X, Liu J, Liu W (2014) Early ischemic blood brain barrier damage: a potential indicator for hemorrhagic transformation following tissue plasminogen activator (tPA) thrombolysis? Curr Neurovasc Res 11(3):254–262

    Article  CAS  PubMed  Google Scholar 

  14. Nishioku T, Dohgu S, Takata F et al (2009) Detachment of brain pericytes from the basal lamina is involved in disruption of the blood–brain barrier caused by lipopolysaccharide-induced sepsis in mice. Cell Mol Neurobiol 29(3):309–316

    Article  CAS  PubMed  Google Scholar 

  15. Andreasen AS, Krabbe KS, Krogh-Madsen R et al (2008) Human endotoxemia as a model of systemic inflammation. Curr Med Chem 15(17):1697–1705

    Article  CAS  PubMed  Google Scholar 

  16. Erikson K, Tuominen H, Vakkala M et al (2020) Brain tight junction protein expression in sepsis in an autopsy series. Crit Care 24(1):385

    Article  PubMed  PubMed Central  Google Scholar 

  17. Guo F, Tang J, Zhou Z et al (2012) GEF-H1-RhoA signaling pathway mediates LPS-induced NF-kappaB transactivation and IL-8 synthesis in endothelial cells. Mol Immunol 50(1–2):98–107

    Article  CAS  PubMed  Google Scholar 

  18. Weighardt H, Holzmann B (2007) Role of Toll-like receptor responses for sepsis pathogenesis. Immunobiology 212(9–10):715–722

    CAS  PubMed  Google Scholar 

  19. Ni Y, Teng T, Li R et al (2017) TNFalpha alters occludin and cerebral endothelial permeability: role of p38MAPK. PLoS ONE 12(2):e0170346

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sankowski R, Mader S, Valdes-Ferrer SI (2015) Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci 9:28

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nwafor DC, Brichacek AL, Mohammad AS et al (2019) Targeting the blood–brain barrier to prevent sepsis-associated cognitive impairment. J Cent Nerv Syst Dis 11:1179573519840652

    Article  PubMed  PubMed Central  Google Scholar 

  22. Haileselassie B, Joshi AU, Minhas PS et al (2020) Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood–brain barrier in septic encephalopathy. J Neuroinflamm 17(1):36

    Article  CAS  Google Scholar 

  23. Vutukuri R, Brunkhorst R, Kestner RI et al (2018) Alteration of sphingolipid metabolism as a putative mechanism underlying LPS-induced BBB disruption. J Neurochem 144(2):172–185

    Article  CAS  PubMed  Google Scholar 

  24. Qin LH, Huang W, Mo XA et al (2015) LPS induces occludin dysregulation in cerebral microvascular endothelial cells via MAPK signaling and augmenting MMP-2 levels. Oxid Med Cell Longev. 2015:120641

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hu Y, Bi Y, Yao D et al (2019) Omi/HtrA2 protease associated cell apoptosis participates in blood–brain barrier dysfunction. Front Mol Neurosci 12:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dahl RH, Berg RMG, Taudorf S et al (2018) A reassessment of the blood–brain barrier transport of large neutral amino acids during acute systemic inflammation in humans. Clin Physiol Funct Imaging 38(4):656–662

    Article  CAS  PubMed  Google Scholar 

  27. Hughes CG, Patel MB, Pandharipande PP (2012) Pathophysiology of acute brain dysfunction: what’s the cause of all this confusion? Curr Opin Crit Care 18(5):518–526

    Article  PubMed  Google Scholar 

  28. Griton M, Dhaya I, Nicolas R et al (2020) Experimental sepsis-associated encephalopathy is accompanied by altered cerebral blood perfusion and water diffusion and related to changes in cyclooxygenase-2 expression and glial cell morphology but not to blood-brain barrier breakdown. Brain Behav Immun 83:200–213

    Article  CAS  PubMed  Google Scholar 

  29. Willie CK, Tzeng YC, Fisher JA et al (2014) Integrative regulation of human brain blood flow. J Physiol 592(5):841–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taccone FS, Su F, Pierrakos C et al (2010) Cerebral microcirculation is impaired during sepsis: an experimental study. Crit Care 14(4):R140

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ferlini L, Su F, Creteur J et al (2020) Cerebral autoregulation and neurovascular coupling are progressively impaired during septic shock: an experimental study. Intensive Care Med Exp 8(1):44

    Article  PubMed  PubMed Central  Google Scholar 

  32. Taccone FS, Su F, De Deyne C et al (2014) Sepsis is associated with altered cerebral microcirculation and tissue hypoxia in experimental peritonitis. Crit Care Med 42(2):e114–e122

    Article  PubMed  Google Scholar 

  33. Faraci FM, Taugher RJ, Lynch C et al (2019) Acid-sensing ion channels: novel mediators of cerebral vascular responses. Circ Res 125(10):907–920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hoiland RL, Fisher JA, Ainslie PN (2019) Regulation of the cerebral circulation by arterial carbon dioxide. Compr Physiol 9(3):1101–1154

    Article  PubMed  Google Scholar 

  35. Taccone FS, Castanares-Zapatero D, Peres-Bota D 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 

  36. Zhou Q, Cao B, Niu L et al (2010) Effects of permissive hypercapnia on transient global cerebral ischemia-reperfusion injury in rats. Anesthesiology 112(2):288–297

    Article  PubMed  Google Scholar 

  37. Van Der Kleij LA, De Vis JB, De Bresser J et al (2020) Arterial CO2 pressure changes during hypercapnia are associated with changes in brain parenchymal volume. Eur Radiol Exp 4(1):17

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bothwell SW, Janigro D, Patabendige A (2019) Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids Barriers CNS 16(1):9

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhao Z, Nelson AR, Betsholtz C et al (2015) Establishment and dysfunction of the blood–brain barrier. Cell 163(5):1064–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339(6116):156–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Da Fonseca AC, Matias D, Garcia C et al (2014) The impact of microglial activation on blood–brain barrier in brain diseases. Front Cell Neurosci 8:362

    Article  PubMed  PubMed Central  Google Scholar 

  42. Moraes CA, Zaverucha-Do-Valle C, Fleurance R et al (2021) Neuroinflammation in sepsis: molecular pathways of microglia activation. Pharmaceuticals (Basel) 14(5):416

    Article  CAS  Google Scholar 

  43. Hickman S, Izzy S, Sen P et al (2018) Microglia in neurodegeneration. Nat Neurosci 21(10):1359–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Melief J, Koning N, Schuurman KG et al (2012) Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia 60(10):1506–1517

    Article  PubMed  Google Scholar 

  45. Heming N, Mazeraud A, Verdonk F et al (2017) Neuroanatomy of sepsis-associated encephalopathy. Crit Care 21(1):65

    Article  PubMed  PubMed Central  Google Scholar 

  46. Michels M, Steckert AV, Quevedo J et al (2015) Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells. Intensive Care Med Exp 3(1):30

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kaushal V, Schlichter LC (2008) Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 28(9):2221–2230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Michels M, Danieslki LG, Vieira A et al (2015) CD40–CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-term cognitive dysfunction after sepsis. Mol Med 21:219–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Danielski LG, Giustina AD, Badawy M 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 

  50. Han Q, Lin Q, Huang P et al (2017) Microglia-derived IL-1beta contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats. J Neuroinflamm 14(1):52

    Article  Google Scholar 

  51. Kacimi R, Giffard RG, Yenari MA (2011) Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappaB, JAK-STAT and JNK stress kinase pathways. J Inflamm (Lond) 8:7

    Article  CAS  Google Scholar 

  52. Michels M, Vieira AS, Vuolo F et al (2015) The role of microglia activation in the development of sepsis-induced long-term cognitive impairment. Brain Behav Immun 43:54–59

    Article  CAS  PubMed  Google Scholar 

  53. Zhao YZ, Gao ZY, Ma LQ et al (2017) Research on biogenesis of mitochondria in astrocytes in sepsis-associated encephalopathy models. Eur Rev Med Pharmacol Sci 21(17):3924–3934

    PubMed  Google Scholar 

  54. Chen XL, Wang Y, Peng WW et al (2018) Effects of interleukin-6 and IL-6/AMPK signaling pathway on mitochondrial biogenesis and astrocytes viability under experimental septic condition. Int Immunopharmacol 59:287–294

    Article  CAS  PubMed  Google Scholar 

  55. Korcok J, Wu F, Tyml K et al (2002) Sepsis inhibits reduction of dehydroascorbic acid and accumulation of ascorbate in astroglial cultures: intracellular ascorbate depletion increases nitric oxide synthase induction and glutamate uptake inhibition. J Neurochem 81(1):185–193

    Article  CAS  PubMed  Google Scholar 

  56. Hasegawa-Ishii S, Inaba M, Umegaki H et al (2016) Endotoxemia-induced cytokine-mediated responses of hippocampal astrocytes transmitted by cells of the brain-immune interface. Sci Rep 6:25457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Parajuli B, Horiuchi H, Mizuno T et al (2015) CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia. Glia 63(12):2274–2284

    Article  PubMed  Google Scholar 

  58. Villeda SA, Luo J, Mosher KI et al (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477(7362):90–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fernandes A, Silva RF, Falcao AS et al (2004) Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS. J Neuroimmunol 153(1–2):64–75

    Article  CAS  PubMed  Google Scholar 

  60. Montoya A, Elgueta D, Campos J et al (2019) Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation. J Neuroinflamm 16(1):258

    Article  CAS  Google Scholar 

  61. Rossaint J, Margraf A, Zarbock A (2018) Role of platelets in leukocyte recruitment and resolution of inflammation. Front Immunol 9:2712

    Article  PubMed  PubMed Central  Google Scholar 

  62. Giles JA, Greenhalgh AD, Denes A et al (2018) Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbalpha. Immunology 154(2):322–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Margraf A, Ley K, Zarbock A (2019) Neutrophil recruitment: from model systems to tissue-specific patterns. Trends Immunol 40(7):613–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Peng X, Luo Z, He S et al (2021) Blood–brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy. Front Cell Infect Microbiol 11:768108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu F, Chen X, Zhai L et al (2020) CXCR2 antagonist attenuates neutrophil transmigration into brain in a murine model of LPS induced neuroinflammation. Biochem Biophys Res Commun 529(3):839–845

    Article  CAS  PubMed  Google Scholar 

  66. Wu F, Zhao Y, Jiao T et al (2015) CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation. J Neuroinflamm 12:98

    Article  Google Scholar 

  67. Zhou H, Andonegui G, Wong CH et al (2009) Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol 183(8):5244–5250

    Article  CAS  PubMed  Google Scholar 

  68. Zarbato GF, De Souza Goldim MP, Giustina AD et al (2018) Dimethyl fumarate limits neuroinflammation and oxidative stress and improves cognitive impairment after polymicrobial sepsis. Neurotox Res 34(3):418–430

    Article  CAS  PubMed  Google Scholar 

  69. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Krizbai IA, Bauer H, Bresgen N et al (2005) Effect of oxidative stress on the junctional proteins of cultured cerebral endothelial cells. Cell Mol Neurobiol 25(1):129–139

    Article  CAS  PubMed  Google Scholar 

  71. Turner RJ, Sharp FR (2016) Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci 10:56

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kenne E, Erlandsson A, Lindbom L et al (2012) Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice. J Neuroinflamm 9:17

    Article  Google Scholar 

  73. Andonegui G, Zelinski EL, Schubert CL et al (2018) Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment. JCI Insight 3(9):1–8

    Article  Google Scholar 

  74. Van Gool WA, Van De Beek D, Eikelenboom P (2010) Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375(9716):773–775

    Article  PubMed  Google Scholar 

  75. Zaghloul N, Addorisio ME, Silverman HA et al (2017) Forebrain cholinergic dysfunction and systemic and brain inflammation in murine sepsis survivors. Front Immunol 8:1673

    Article  PubMed  PubMed Central  Google Scholar 

  76. Erbas O, Taskiran D (2014) Sepsis-induced changes in behavioral stereotypy in rats; involvement of tumor necrosis factor-alpha, oxidative stress, and dopamine turnover. J Surg Res 186(1):262–268

    Article  CAS  PubMed  Google Scholar 

  77. Freund HR, Muggia-Sullam M, Lafrance R et al (1986) Regional brain amino acid and neurotransmitter derangements during abdominal sepsis and septic encephalopathy in the rat. The effect of amino acid infusions. Arch Surg 121(2):209–216

    Article  CAS  PubMed  Google Scholar 

  78. Gyoneva S, Traynelis SF (2013) Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors. J Biol Chem 288(21):15291–15302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Leon A, Lepouse C, Floch T et al (2006) Brain injury during severe sepsis. Ann Fr Anesth Reanim 25(8):863–867

    Article  CAS  PubMed  Google Scholar 

  80. Acharya S, Kim KM (2021) Roles of the functional interaction between brain cholinergic and dopaminergic systems in the pathogenesis and treatment of schizophrenia and Parkinson’s disease. Int J Mol Sci 22(9):1–8

    Article  Google Scholar 

  81. Bugiani O (2021) Why is delirium more frequent in the elderly? Neurol Sci 42(8):3491–3503

    Article  PubMed  PubMed Central  Google Scholar 

  82. Pavlov VA, Wang H, Czura CJ et al (2003) The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 9(5–8):125–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Santos-Junior NN, Catalao CHR, Costa LHA et al (2018) Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus. J Neuroimmunol 324:143–148

    Article  CAS  PubMed  Google Scholar 

  84. Hofer S, Eisenbach C, Lukic IK et al (2008) Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit Care Med 36(2):404–408

    Article  CAS  PubMed  Google Scholar 

  85. Zivkovic AR, Sedlaczek O, Von Haken R et al (2015) Muscarinic M1 receptors modulate endotoxemia-induced loss of synaptic plasticity. Acta Neuropathol Commun 3:67

    Article  PubMed  PubMed Central  Google Scholar 

  86. Van Eijk MM, Roes KC, Honing ML et al (2010) Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 376(9755):1829–1837

    Article  PubMed  Google Scholar 

  87. Tomasi CD, Salluh J, Soares M et al (2015) Baseline acetylcholinesterase activity and serotonin plasma levels are not associated with delirium in critically ill patients. Rev Bras Ter Intensiva 27(2):170–177

    Article  PubMed  PubMed Central  Google Scholar 

  88. Liu A, Ding S (2019) Anti-inflammatory effects of dopamine in lipopolysaccharide (LPS)-stimulated RAW264.7 cells via inhibiting NLRP3 inflammasome activation. Ann Clin Lab Sci 49(3):353–360

    CAS  PubMed  Google Scholar 

  89. Rangel-Barajas C, Coronel I, Floran B (2015) Dopamine receptors and neurodegeneration. Aging Dis 6(5):349–368

    Article  PubMed  PubMed Central  Google Scholar 

  90. Bissonette GB, Roesch MR (2016) Development and function of the midbrain dopamine system: what we know and what we need to. Genes Brain Behav 15(1):62–73

    Article  CAS  PubMed  Google Scholar 

  91. Sommer BR, Wise LC, Kraemer HC (2002) Is dopamine administration possibly a risk factor for delirium? Crit Care Med 30(7):1508–1511

    Article  CAS  PubMed  Google Scholar 

  92. Freund HR, Muggia-Sullam M, Peiser J et al (1985) Brain neurotransmitter profile is deranged during sepsis and septic encephalopathy in the rat. J Surg Res 38(3):267–271

    Article  CAS  PubMed  Google Scholar 

  93. Shimizu I, Adachi N, Liu K et al (1999) Sepsis facilitates brain serotonin activity and impairs learning ability in rats. Brain Res 830(1):94–100

    Article  CAS  PubMed  Google Scholar 

  94. Nolan RA, Reeb KL, Rong Y et al (2020) Dopamine activates NF-kappaB and primes the NLRP3 inflammasome in primary human macrophages. Brain Behav Immun Health 2:17

    Google Scholar 

  95. Li F, Zhang B, Duan S et al (2020) Small dose of L-dopa/benserazide hydrochloride improved sepsis-induced neuroinflammation and long-term cognitive dysfunction in sepsis mice. Brain Res 1737:146780

    Article  CAS  PubMed  Google Scholar 

  96. Beis D, Holzwarth K, Flinders M et al (2015) Brain serotonin deficiency leads to social communication deficits in mice. Biol Lett 11(3):1–8

    Article  CAS  Google Scholar 

  97. Bengtsson F, Bugge M, Hansson L et al (1987) Serotonin metabolism in the central nervous system following sepsis or portacaval shunt in the rat. J Surg Res 43(5):420–429

    Article  CAS  PubMed  Google Scholar 

  98. O’dell TJ, Connor SA, Guglietta R et al (2015) beta-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learn Mem 22(9):461–471

    Article  PubMed  PubMed Central  Google Scholar 

  99. Xu H, Rajsombath MM, Weikop P et al (2018) Enriched environment enhances beta-adrenergic signaling to prevent microglia inflammation by amyloid-beta. EMBO Mol Med 10(9):1–7

    Article  CAS  Google Scholar 

  100. Manczak EM, Dougherty B, Chen E (2019) Parental depressive symptoms potentiate the effect of youth negative mood symptoms on gene expression in children with asthma. J Abnorm Child Psychol 47(1):99–108

    Article  PubMed  PubMed Central  Google Scholar 

  101. Zong MM, Zhou ZQ, Ji MH et al (2019) Activation of beta2-adrenoceptor attenuates sepsis-induced hippocampus-dependent cognitive impairments by reversing neuroinflammation and synaptic abnormalities. Front Cell Neurosci 13:293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Obata K (2013) Synaptic inhibition and gamma-aminobutyric acid in the mammalian central nervous system. Proc Jpn Acad Ser B 89(4):139–156

    Article  CAS  Google Scholar 

  103. Sallam MY, El-Gowilly SM, Abdel-Galil AG et al (2016) Central GABAA receptors are involved in inflammatory and cardiovascular consequences of endotoxemia in conscious rats. Naunyn Schmiedebergs Arch Pharmacol 389(3):279–288

    Article  CAS  PubMed  Google Scholar 

  104. Dadsetan S, Balzano T, Forteza J et al (2016) Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy. J Neuroinflamm 13(1):245

    Article  Google Scholar 

  105. Serantes R, Arnalich F, Figueroa M et al (2006) Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy. J Biol Chem 281(21):14632–14643

    Article  CAS  PubMed  Google Scholar 

  106. Wang DS, Zurek AA, Lecker I et al (2012) Memory deficits induced by inflammation are regulated by alpha5-subunit-containing GABAA receptors. Cell Rep 2(3):488–496

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

First and foremost, I would like to show my deepest gratitude to my supervisor, Professor Wenlan Liu, a kind, responsible and resourceful scholar, who has provided me with valuable guidance in every stage of scientific research. In addition, I would like to thank the anonymous reviewers for their helpful remarks.

Funding

The work was supported by Guangdong Innovation Platform of Translational Research for Cerebrovascular Diseases and grants from National Natural Science Foundation of China (Grant No. 81760227, 81873747), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2019A1515010311) and Science and Technology Innovation Commission of Shenzhen Municipality (Grant Nos. GJHZ20190820115001765, JCYJ20180507184656626).

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Authors and Affiliations

  1. Department of Intensive Care Unit, ZhuHai People’s Hospital, 79 KangNing Road, XiangZhou District, ZhuHai, China

    Ke Yang

  2. Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University Health Science Center, 3002 SunGang West Road, FuTian District, ShenZhen, 518035, China

    Ke Yang & Yuan Zhang

  3. Department of Orthopedic, ZhuHai People’s Hospital, 79 KangNing Road, XiangZhou District, ZhuHai, China

    JinQuan Chen

  4. Department of Neurology, DongHua Hospital, 1 East Road, East Side, DongGuan, China

    Ting Wang

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  1. Ke Yang
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  3. Ting Wang
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  4. Yuan Zhang
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KY had the idea for the article and drafted the work. JQC and TW performed the literature search, and YZ critically wrote and revised the manuscript.

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Correspondence to Yuan Zhang.

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Yang, K., Chen, J., Wang, T. et al. Pathogenesis of sepsis-associated encephalopathy: more than blood–brain barrier dysfunction. Mol Biol Rep 49, 10091–10099 (2022). https://doi.org/10.1007/s11033-022-07592-x

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