Sepsis-Associated Encephalopathy: Insight into Injury and Pathogenesis

Zhao, Lina; Gao, Yanxia; Guo, Shigong; Lü, Xin; Yu, Shiyuan; Ge, Zeng Zheng; Zhu, Hua; Li, Yang

doi:10.2174/1871527319999201117122158

Cited by 17 publications

(24 citation statements)

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“…Neuroinflammation and destruction of BBB also played an important role in the cognitive impairment of SAE. , Consistent with above findings, our results demonstrated that destruction of BBB as well as proinflammatory reactions were significantly activated, which contributed to the cognitive impairment of SAE. Increasing evidence suggested that excessive glutamate production increased the permeability of BBB via NMDA receptor dependent mechanism .…”

Section: Discussionsupporting

confidence: 90%

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

Zheng,

Li,

Xiang

et al. 2023

ACS Omega

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Sepsis-associated encephalopathy (SAE) is the most common complication of sepsis, with increased morbidity and mortality. To date, there has still been no established pharmacological therapy. Memantine, as an NMDA (N-methyl-Daspartate) receptor antagonist, exhibited neuroprotective effects against cognitive and emotional dysfunction in many disorders. We performed cecal ligation and puncture (CLP) inducing sepsis as the ideal animal model of SAE. CLP-induced septic mice were given a memantine treatment through intragastric administration. The novel object recognition test indicated that memantine significantly improved cognitive dysfunction in septic mice. The open field test revealed that the anxiety-like behaviors and locomotion ability of septic mice were relieved by memantine. The pole test further confirmed the protective effects of memantine against immobility. Memantine significantly inhibited the excessive glutamate production and improved impaired neurogenesis on first and seventh day after sepsis, accompanying with reducing proinflammatory cytokines production (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1beta (IL-1β), and IL-10) and microglia activation in the brain of SAE. In addition, memantine treatment also reducing sepsis-induced brain blood barrier disruption via inhibiting the expression of metalloproteinase-9 (MMP-9). In conclusion, memantine exerted neuro-protective effects against cognitive and emotional defects, which might be considered as a promising therapy for SAE.

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Section: Discussionsupporting

confidence: 90%

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

Zheng,

Li,

Xiang

et al. 2023

ACS Omega

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“…In addition, the CNS through the hypothalamic-pituitary-adrenal (HPA) axis, gut-brain axis, sympathetic and parasympathetic nervous system, function as a transportation hub ( 8 , 13 ). The immuno-inflammatory signals affect different regions of the brain, mainly through humoral and neural pathways, which mostly involve damage of the BBB and activation of vagal afferent fibers, respectively ( 4 , 5 , 8 , 59 ). At the same time, CNS dysfunction may be an important cause of neuroendocrine-immune network breakdown, as well as a potential therapeutic target (such as cholinergic anti-inflammatory pathway, humoral pathway mediated by vasopressin, and reconstruction of the HPA axis) for sepsis-induced immunosuppression or endocrine dysfunction ( 19 , 63 , 118 ).…”

Section: T Regs -Related Therapeutic Potential In Saementioning

confidence: 99%

“…T regs seem to be key players in the development of sepsis, as well as the hotspot strategies in immunotherapy and immune checkpoints of sepsis and sepsisassociated complications. However, the dual functions of T regs in infections may provide beneficial or harmful effects even though the number of CD3 + CD4 + CD25 hi CD127 lo T regs in the early stage of sepsis (within 3 days) is not associated with the outcomes (36)(37)(38)(39)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59).…”

Section: Sae and Regulatory T Cellsmentioning

confidence: 99%

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy

et al. 2022

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Sepsis-associated encephalopathy (SAE) is a diffuse central nervous system (CNS) dysfunction during sepsis, and is associated with increased mortality and poor outcomes in septic patients. Despite the high incidence and clinical relevance, the exact mechanisms driving SAE pathogenesis are not yet fully understood, and no specific therapeutic strategies are available. Regulatory T cells (Tregs) have a role in SAE pathogenesis, thought to be related with alleviation of sepsis-induced hyper-inflammation and immune responses, promotion of T helper (Th) 2 cells functional shift, neuroinflammation resolution, improvement of the blood-brain barrier (BBB) function, among others. Moreover, in a clinical point of view, these cells have the potential value of improving neurological and psychiatric/mental symptoms in SAE patients. This review aims to provide a general overview of SAE from its initial clinical presentation to long-term cognitive impairment and summarizes the main features of its pathogenesis. Additionally, a detailed overview on the main mechanisms by which Tregs may impact SAE pathogenesis is given. Finally, and considering that Tregs may be a novel target for immunomodulatory intervention in SAE, different therapeutic options, aiming to boost peripheral and brain infiltration of Tregs, are discussed.

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“…Clinical studies had found that in about 70% of sepsis patients with cognitive dysfunction after sepsis progresses to encephalopathy in in critically ill patients and perioperative period (2), the patient's hospital stay is prolonged, the cost of hospitalization increases, and the mortality rate is about 60% (3). The pathogenesis of SAE includes an inflammatory response, astrocytes and microglia activation, mitochondrial dysfunction, and the impaired bloodbrain barrier (4)(5)(6). SAE has a high incidence and poor prognosis, but its pathogenesis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α/BNIP3L induced cognitive deficits in a mouse model of sepsis-associated encephalopathy

et al. 2022

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ObjectiveSepsis Associated Encephalopathy (SAE) is a common complication in critically ill patients and perioperative period, but its pathogenesis is still unclear. This study aimed to explore the effect of the HIF-1α (hypoxia-inducible factor-1α)/BNIP3L (Bcl-2/adenovirus E1B 19-kDa interaction protein) signaling pathway on SAE.MethodsC57BL/6J male mice were divided into four groups, using a random number table method: control group, sham group, sepsis group, sepsis+HIF-1α activity inhibitor (echinomycin) group. Sepsis was induced by cecal ligation and puncture (CLP). At 24 h after surgery, brain tissue was sampled. HE was staining to observe changes in the hippocampus structure. Fluoroscopy observes changes in mitochondrial structure. Western blot, QT-PCR, and immunofluorescence were used to assess the amount of expression of HIF-1α and BNIP3L in the hippocampus and mitochondrion of hippocampus neurons. Observation of neuronal apoptosis by TUNEL staining. Seven days after surgery, mice were tested in a Morris water maze test to assess cognitive function after CLP.ResultsOur results show that CLP-induced hippocampus-dependent cognitive deficits were accompanied with increased HIF 1a and decreased BNIP3L, increased protein levels of TNF-α, IL-6, and IL-β, and damage to mitochondrial structures and neuronal apoptosis in the hippocampus. In addition, administration of echinomycin rescues cognitive deficits, ameliorates HIF-1α and BNIP3L-mediated neuronal pyroptosis and damaged mitochondrial structures, and decreases the expression of TNF-α and IL-6 in the hippocampus.ConclusionsHIF-1α and the BNIP3L promote mitochondrial damage, and neuronal apoptosis and the expression of inflammatory factors may be the mechanism of SAE in critically ill patients and perioperative period

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Sepsis-Associated Encephalopathy: Insight into Injury and Pathogenesis

Cited by 17 publications

References 0 publications

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy

HIF-1α/BNIP3L induced cognitive deficits in a mouse model of sepsis-associated encephalopathy

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