Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus

Santos-Júnior, Nilton Nascimento; Catalão, Carlos Henrique Rocha; Costa, Luís Henrique Angenendt da; Souza, Anderson Oliveira; Mota, Clarissa M.D.; Alberici, Luciane C.; Branco, Luiz G.S.; Rocha, Maria José Alves da

doi:10.1016/j.jneuroim.2018.08.013

Cited by 23 publications

(14 citation statements)

References 48 publications

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“…Furthermore, at the early stages of neuroinflammation, it is able to cause neurotoxicity [ 62 ]. Meanwhile, IL-6 can induce cyclooxygenase-2 (COX-2) expression, which in turn increases the levels of the vasodilatory prostaglandin I2 (PGI 2 ) [ 31 , 63 ], causing fever and behavioral disturbances [ 5 ]. Endothelial adhesion molecules, such as V-CAM and I-CAM, also increase their expression in cerebrovascular endothelial cells, increasing the permeability of the BBB [ 5 , 31 , 64 ] and allowing the transfer of toxic factors from the peripheral circulation to the brain [ 12 , 27 ], causing the BBB loss of selectivity, leading to neuroinflammation and microglia activation [ 65 ].…”

Section: Physiopathology Of Saementioning

confidence: 99%

“…Furthermore, this reduction causes a decreased cholinergic inhibition of activated microglia, thus accelerating the microglia activation and, in turn, increasing the cytokine levels [ 69 ]. In addition, microglial activation causes hypothalamic neuroinflammation triggering neurologic alterations such as neurotransmission disturbances, as can be the release increment of glucocorticoid hormone or a cell death increment [ 6 , 63 ]. This cascade leads to the immunosuppressive response, characteristic of sepsis and SAE, and exacerbates the infection worsening the outcome [ 69 ].…”

Section: Physiopathology Of Saementioning

confidence: 99%

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Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

et al. 2021

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Sepsis-associated encephalopathy (SAE) is a neurological complication of sepsis, characterized by brain dysfunction without any direct central nervous system infection. The diagnosis of SAE is currently a challenge. In fact, problems in making a diagnosis of SAE cause a great variability of incidence that can reach up to 70% of all septic patients. Even more, despite SAE is the most frequent type of encephalopathy occurring in critically ill patients, the molecular mechanisms that guide its progression have not been completely elucidated. On the other hand, miRNAs have proven to be excellent biomarkers for both diagnosis and prognosis, especially in brain pathologies because of their small size they can cross the blood–brain barrier easier than other biomolecules. The identification of new miRNAs as biomarkers may help to improve SAE diagnosis and prognosis and also to design new therapies for this clinical manifestation that produces diffuse cerebral dysfunction. This review is focused on SAE physiopathology and the need to have clear criteria for its diagnosis; thus, this work postulates some miRNA candidates to be used for SAE biomarkers because of their role in both, neurological damage and sepsis.

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Section: Physiopathology Of Saementioning

confidence: 99%

Section: Physiopathology Of Saementioning

confidence: 99%

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

et al. 2021

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“…The mortality rate of SAE patients has been reported to be from 26 to 49% higher than that of septic patients without neurological manifestations [4]. Several mechanisms have been proposed regarding the pathogenesis of SAE, these include the dysfunction of blood-brain barrier, the effect of endotoxins, the effect of inflammatory mediators [5,6], neurovascular coupling [7], regulation of vagus nerve [8], and the vicious cycle between brain injury and a progressively aberrant immune response [9]. Nonetheless, there is a lack of effective clinical intervention for SAE currently.…”

Section: Introductionmentioning

confidence: 99%

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

Luo

Zhong

et al. 2020

J Neuroinflammation

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Background: Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE. Methods: Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg −1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice. Results: In the septic mice, cognitive function was impaired, the percentage of CD4 + T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the antiinflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg −1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4 + T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4 + T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4 + T cells in cultured splenocytes from septic mice (P = 0.0021). Conclusion: Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4 + T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/antiinflammatory homeostasis.

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“…Finally, sepsis interferes with the “inflammatory reflex,” a negative feedback loop in the vagus nerve where ascending signals “inform” the brain of inflammatory events in the periphery while descending signals limit the cytokine response to those same responses ( 28 – 31 ). A number of studies have demonstrated brain inflammation in experimental sepsis, most often implicating microglia ( 29 , 30 ).…”

Section: Overview Of the Presentationmentioning

confidence: 99%

The Surviving Sepsis Campaign: Basic/Translational Science Research Priorities*

Deutschman

Hellman

Ferrer

et al. 2020

Critical Care Medicine

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Objectives: Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources: Original paper, search of the literature. Study Selection: By several members of the original task force with specific expertise in basic/translational science. Data Extraction: None. Data Synthesis: None. Conclusions: In the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives.

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Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus

Cited by 23 publications

References 48 publications

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

The Surviving Sepsis Campaign: Basic/Translational Science Research Priorities*

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