TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF

Calsavara, Allan Jefferson Cruz; Soriani, Frederico Marianetti; Vieira, Leda Quércia; Costa, Priscila A.; Rachid, Milene Alvarenga; Teixeira, Antônio Lúcio

doi:10.1007/s11011-014-9610-8

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…e CLP procedure is a well-established, clinically germane method for generating models used in sepsis research [8,9]. Mice with severe CLP-induced sepsis exhibit increased damage, compared with nonseptic mice.…”

Section: Discussionmentioning

confidence: 99%

“…For example, treatment with zinc protoporphyrin IX (ZnPPIX) prior to cecal ligation and puncture (CLP) was associated with increased proinflammatory cytokine levels 6 h after the procedure [7]. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) is increasingly recognized as an important regulator of basal and induced expression of a range of antioxidant response element-dependent genes [8,9]. us, Nrf2 regulates both physiological and pathophysiological responses to the presence of oxidants [10].…”

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Hydrogen on Myocardial Mitochondrial Functions in Septic Mice

Zhang

Dong

Xie

et al. 2020

BioMed Research International

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Enhancement of mitochondrial physiological function prevents sepsis-induced dysfunction. The present study aimed to elucidate the mechanism by which hydrogen (H2) affects mitochondrial function in a wild-type (WT) and homozygous nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (KO, Nrf2−/−) murine model of sepsis. In myocardial tissues with severe sepsis, H2 gas treatment reduced mitochondrial dysfunction, whereas zinc protoporphyrin (ZnPPIX) negated these beneficial effects. H2 treatment upregulated the protein expression of mitofusin-2 (Mfn2), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and protein heme oxygenase-1 (HO-1) in WT mice with severe sepsis but not in their Nrf2−/− counterparts, and this upregulation was inhibited in the presence of ZnPPIX. In conclusion, the mechanism by which H2 limits organ damage in mice with severe sepsis involves HO-1, whereas the mechanism that limits severe sepsis-related mitochondrial dysfunction involves both HO-1 and Nrf2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective Effects of Hydrogen on Myocardial Mitochondrial Functions in Septic Mice

Zhang

Dong

Xie

et al. 2020

BioMed Research International

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“…Survivors of severe infection have a high prevalence of substantial depressive symptoms and memory deficit, but beginning interventions before hospital discharge may improve functional outcomes (Davydow et al, 2013; Calsavara et al, 2015). In the present study, we found that LPS can cause long-term depressive-like behaviors and memory deficit in mice, as evidenced by results from the tail suspension test, the forced swim test, the sucrose preference test, and the novel object recognition test.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide

et al. 2017

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Lipopolysaccharide (LPS) might affect the central nervous system by causing neuroinflammation, which subsequently leads to brain damage and dysfunction. In this study, we evaluated the role of nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation in long-term behavioral alterations of 8-week-old male C57BL/6 mice injected intraperitoneally with LPS (5 mg/kg). At different time points after injection, we assessed locomotor function with a 24-point neurologic deficit scoring system and the rotarod test; assessed recognition memory with the novel object recognition test; and assessed emotional abnormality (anhedonia and behavioral despair) with the tail suspension test, forced swim test, and sucrose preference test. We also assessed protein expression of NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1 p10 in hippocampus by Western blotting; measured levels of interleukin (IL)-1β, IL-18, tumor necrosis factor α (TNFα), and IL-10 in hippocampus; measured TNFα and IL-1β in serum by ELISA; and evaluated microglial activity in hippocampus by Iba1 immunofluorescence. We found that LPS-injected mice displayed long-term depression-like behaviors and recognition memory deficit; elevated expression of NLRP3, ASC, and caspase-1 p10; increased levels of IL-1β, IL-18, and TNFα; decreased levels of IL-10; and increased microglial activation. These effects were blocked by the NLRP3 inflammasome inhibitor Ac-Tyr-Val-Ala-Asp-chloromethylketone. The results demonstrate proof of concept that NLRP3 inflammasome activation contributes to long-term behavioral alterations in LPS-exposed mice, probably through enhanced inflammation, and that NLRP3 inflammasome inhibition might alleviate peripheral and brain inflammation and thereby ameliorate long-term behavioral alterations in LPS-exposed mice.

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“…It has been suggested that TNFR1 is a critical mediator in the onset of SAE because of its stimulating effects on aquaporin-4 and concomitant increase in water content [70]. Interestingly, TNFR1 -/-mice also experienced less sepsis-induced memory deficits, possibly by increased hippocampal expression of BDNF [71]. However, despite of these interesting observations, TNFR1 KO mice were not protected against very high LPS doses [39,63], which of 59 our lab also confirmed in previous research [67].…”

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsismentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF

Cited by 22 publications

References 39 publications

Protective Effects of Hydrogen on Myocardial Mitochondrial Functions in Septic Mice

Protective Effects of Hydrogen on Myocardial Mitochondrial Functions in Septic Mice

NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide

A New Venue of TNF Targeting

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