Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis

Xie, Xia; Liu, Lu; Wang, Yuchang; Wang, Chuntao; Zheng, Qiang; Liu, Qinxin; Li, Zhanfei; Bai, Xiangjun; Liu, Xinghua

doi:10.1016/j.bbi.2019.05.038

Cited by 147 publications

(112 citation statements)

References 72 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…In the present study, we chose 5 mg kg −1 LPS to establish the SAE mouse model. Consistent with previous studies [29,30], 5 mg kg −1 LPS injection severely impaired fear memory as indicated by decreased freezing time in both context and cued fear conditioning testing with reversible changes in weight of the mice. In this case, it is a reliable SAE model for the evaluation of changed cognitive function.…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

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

Luo

Zhong

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

“…Several SAE animal models have been established, such as cecal ligation and puncture (CLP) and LPS i.p. injection [29,30]. Although CLP method has been considered the classical animal model for sepsis [31], LPS-induced endotoxemia is also frequently used to mimic sepsis as it leads to sudden and severe systemic inflammation in rodents [32].…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…Our ultrastructural findings further implicate neuronal pyroptosis in cerebral ischemia. The disruption of plasma and nuclear membranes had been noted previously in an EM study of cancer cells during chemotherapy and in neurons in sepsis‐associated encephalopathy 39‐41 . A similar breakdown of mitochondria was revealed in a live‐cell analysis of triggered bone marrow‐derived macrophages 24 .…”

Section: Discussionsupporting

confidence: 68%

Caspase‐1 inhibition prevents neuronal death by targeting the canonical inflammasome pathway of pyroptosis in a murine model of cerebral ischemia

Hao

Yao

et al. 2020

CNS Neurosci Ther

View full text Add to dashboard Cite

Aims The involvement of pyroptosis in ischemic stroke remains to be established. Therefore, we used the specific pyroptosis inhibitor Vx765 as an experimental intervention target in a murine model of stroke. Methods A total of 564 C57BL/6 mice were subjected to photothrombotic procedures and treated via gavage with Vx765 at 1‐hour post‐ischemia. We subsequently assessed the expression of Gasdermin D (GSDMD), inflammasomes, caspase‐1, and interleukin‐1β (IL‐1β) using immunofluorescence (IF) and Western blot (WB) analyses. We also examined ultrastructural changes of cortical neurons with transmission electron microscopy (TEM) and measured infarct volumes dynamically by magnetic resonance imaging (MRI). Moreover, we evaluated the neurologic deficits by modified neurological severity scores, the rotarod test, and Treadscan. Results Elevated expression of GSDMD and GSDMD p30, the pore‐forming subunit, was evident in the peri‐ischemic region on days one and three post‐ischemia. The neuronal plasma, nuclear, and mitochondrial membranes showed ultrastructural damage at day three post‐stroke. Elevated expression of inflammasomes, caspase‐1, and IL‐1β was also present on days one and three post‐injury. There were significant differences between Vx765‐treated and vehicle groups in mean infarct volumes (14.36 vs 21.52 mm3; 12.34 vs 18.56 mm3; 4.13 vs 10.06 mm3; P < .05 at day one, three, and seven post‐surgery, respectively). Mice treated with Vx765 showed better motor recovery as assessed by serial behavior tests and had better neuronal survival, which was attributable to pyroptosis inhibition, as illustrated by downregulated expression of the effector protein GSDMD, inflammasomes, caspase‐1, and IL‐1β. Besides, treatment with Vx765 preserved neuronal membrane structures after the ischemic injury. Conclusions Pyroptosis emerges as an important pathway for neuronal death in an acute ischemic stroke. Vx765, a low molecular weight drug that has proven safe in clinical epilepsy trials, has potential therapeutic value for cerebral ischemia by targeting the canonical inflammasome pathway of pyroptosis.

show abstract

“…Previous findings confirmed that the level of TNF-α, IL-1β, and IL-6 are elevated within 6 h in sepsis brain tissue and continually increased for 10 to 30 days [33,34]. It is important to note that the increased pro-inflammatory cytokine levels in the brain parenchyma showed a high correlation with memory impairment and the death rate in animal models of sepsis [12,35]. Similarly, we found an increased TNF-α, IL-1β, and IL-6 levels in the serum, the hippocampus, and the frontal cortex at day 1 and day 10 after sepsis onset.…”

Section: Discussionsupporting

confidence: 52%

Qiang Xin 1 Formula Suppresses Excessive Pro-inflammatory Cytokine Responses and Microglia Activation to Prevent Cognitive Impairment and Emotional Dysfunctions in Experimental Sepsis

Wang

Guo

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: Sepsis commonly leads to acute and long-term cognitive and affective impairments which are associated with increased mortality in patients. Neuroinflammation characterized by excessive cytokine release and immune cell activation underlies the behavioral changes associated with sepsis. We previously reported that the administration of a traditional Chinese herbal Qiang Xin 1 (QX1) formula improves survival in septic mice. This study was performed to better understand the effects and the mechanisms of QX1 formula treatment on behavioral changes in septic model. Methods: A preclinical septic model was induced by cecal ligation and puncture in mice. QX1 formula was orally administrated daily. Behavior test including Morris water maze, novel object recognition testing, elevated plus maze and open field testing was performed. Elisa, immunofluorescence, microarray analysis, and Real-time PCR were analyzed. Results: QX1 formula administration significantly improved survival, alleviated overall cognitive impairment and emotional dysfunction in septic mice. QX1 formula administration dramatically inhibited short and long-term excessive pro-inflammatory cytokine production both peripherally and centrally, and was accompanied by diminished microglial activation in septic mice. Biological processes including synaptic transmission, microglia cell activation, cytokine production, microglia cell polarization, as well as inflammatory responses related to signaling pathways including the MAPK signaling pathway and the NF-κB signaling pathway were altered prominently by QX1 formula treatment in the hippocampus of septic mice. In addition, QX1 formula administration decreased the expression of the M1 phenotype microglia gene markers such as Cd32, Socs3, and Cd68, while up-regulated M2 phenotype marker genes including Myc, Arg-1, and Cd206. Conclusions: QX1 formula administration attenuates cognitive deficits, emotional dysfunction, and reduces neuroinflammatory responses to improve survival in septic mice. Diminished microglial activation and altered microglial polarization are involved in the neuroprotective mechanism of QX1 formula.

show abstract

Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis

Cited by 147 publications

References 72 publications

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

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

Caspase‐1 inhibition prevents neuronal death by targeting the canonical inflammasome pathway of pyroptosis in a murine model of cerebral ischemia

Qiang Xin 1 Formula Suppresses Excessive Pro-inflammatory Cytokine Responses and Microglia Activation to Prevent Cognitive Impairment and Emotional Dysfunctions in Experimental Sepsis

Contact Info

Product

Resources

About