Septic encephalopathy: does inflammation drive the brain crazy?

Dal‐Pizzol, Felipe; Tomasi, Cristiane Damiani; Ritter, Cristiane

doi:10.1590/1516-4446-2013-1233

Cited by 70 publications

(61 citation statements)

References 114 publications

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“…Its pathophysiological mechanism is complex and not fully resolved. It may involve brain microvascular endothelial cell dysfunction, destruction of the BBB, cerebral local inflammatory cell infiltration, inflammation medium, reduced cerebral perfusion, cerebral microvascular adjustment disorder, astrocyte and neuron dysfunction, neurotransmitter disorders, mitochondrial dysfunction, apoptosis, oxidative stress, calcium disorders, and so on [1,13,15]. Compelling evidence indicates that oxidative stress, mitochondrial dysfunction, and apoptosis play critical roles in the pathogenesis of SAE [16].…”

Section: Discussionmentioning

confidence: 99%

Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy

Wang

Yao

et al. 2018

Cell Physiol Biochem

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Background/Aims: the pathogenesis of sepsis-associated encephalopathy (SAE) is multifactorial, involving neurotransmitter alterations, inflammatory cytokines, oxidative damage, mitochondrial dysfunction, apoptosis, and other factors. Mitochondria are major producers of reactive oxygen species, resulting in cellular injury. Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell death; it is translocated from mitochondria to the cytosol after an apoptotic insult. We previously found that UCF-101, a specific inhibitor of Omi/HtrA2, has neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats. In this study, the mechanisms and molecular pathways underlying these effects were investigated. Methods: Male Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy and were administered vehicle or UCF-101 (10 µmol/kg). The hippocampus was isolated for subsequent analysis. Omi/HtrA2 expression in the mitochondria or cytosol was evaluated by immunofluorescence or western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was utilized to evaluate levels of apoptosis, and western blotting was used to evaluate apoptosis-related proteins, such as cleaved caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP). Tight junction expression was assessed by immunofluorescence and western blotting. Mitochondrial function, inflammatory cytokines, and oxidative stress were also assayed. In addition, a wet/dry method was used to evaluate brain edema and Evans blue extravasation was used to evaluate blood–brain barrier (BBB) integrity. Results: After CLP treatment, the hippocampus exhibited a mild increase in Omi/HtrA2 expression; cytosolic Omi/HtrA2 expression increased significantly, whereas mitochondrial Omi/HtrA2 expression was reduced, indicating that CLP-induced oxidative stress resulted in the translocation of Omi/HtrA2 from mitochondria to the cytosol. Hippocampal cleaved caspase-3, caspase-9, and PARP levels were significantly higher in animals treated with CLP than in sham-operated animals, while XIAP expression was lower. Treatment with UCF-101 prevented the mobilization of Omi/HtrA2 from mitochondria to the cytosol, attenuated XIAP degradation, and decreased cleaved caspase-3, caspase-9, and PARP expression as well as apoptosis. UCF-101 also reversed the decreased mitochondrial complex I, II, and III respiration and the reduced ATP caused by CLP. In addition, UCF-101 treatment resulted in a significant improvement in BBB integrity, as demonstrated by increased occludin, claudin-5, and zonula occludens 1 levels and reduced Evans blue extravasation. No significant effects of UCF-101 on brain edema were found. Inflammatory cytokines and oxidative stress were significantly higher in the CLP-treated group than in the sham-operated group. However, the inhibition of Omi/HtrA2 by UCF-101 significantly alleviated these responses. Conclusion: Our data indicated that Omi/ HtrA2 regulates a ...

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Section: Discussionmentioning

confidence: 99%

Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy

Wang

Yao

et al. 2018

Cell Physiol Biochem

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“…Actually, for other potent factors related to neurotransmission, norepinephrine [80], adrenergic system [81,82], serotonergic system [83], acetylcholine [84][85][86], gamma-aminobutyric receptor A [87], N-methyl-D-aspartate receptor 2B [29], and brain neurovascular dysfunction [88] were involved in the pathogenesis of SE. In summary, sepsis leads to the aberrant conditions in the neuronal and/or glial environments and may result in the devastating symptoms in the pathogenesis of SE.…”

Section: Imbalance Of Synaptic Transmissions On Neuronsmentioning

confidence: 99%

In Vivo Imaging of Septic Encephalopathy

Imamura¹,

Murakami²,

Matsumoto³

et al. 2017

Sepsis

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Septic encephalopathy is a devastating symptom of severe sepsis. Many studies have been performed to uncover the pathophysiological mechanisms of septic encephalopathy; however, novel technical approaches are still required to overcome this complex symptom. Because patients are suffering from severe cognitive impairment, coma, or delirium, which burden not only patients but also caregivers, overcoming septic encephalopathy is still a major social problem worldwide, especially in the intensive care. Septic encephalopathy seems to be caused by cytokine invasion and/or oxidative stress into the brain, and this pathological state leads to imbalance of neurotransmitters. In addition to this pathophysiology, septic encephalopathy causes complicated symptoms (e.g., ischemic stroke, edema, and aberrant sensory function). For these pathophysiological mechanisms, electrophysiology using animal models, positron emission tomography (PET), computed tomography, and magnetic resonance imaging for septic patients has provided important clues. However, the research for septic encephalopathy is currently confronted with the difficulty of complex symptoms. To overcome this situation, in this chapter, we introduce our novel methods for in vivo imaging of septic encephalopathy using near infrared (NIR) nanoparticles, quantum dots. In addition to our recent progress, we propose a strategy for the future approach to in vivo imaging of septic encephalopathy.

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“…Symptoms of SE include somnolence, stupor, coma, confusion, disorientation, agitation, irritability and a decreased score on the Glasgow Coma Scale. SE was defined as an altered mental status with behavioral or cognitive abnormalities, but there is no current unified standard for SE diagnoses (22,23). Patients suffering from the following underlying conditions that may affect brain and CNS function and symptomatic diagnosis were excluded: i) Intracranial organic diseases; ii) severe nutritional deficiency; iii) hypoglycemia; iv) hypernatremia; v) hepatic encephalopathy; and vi) a history of exposure to drugs, toxic substances, alcohol, industrial agents, heavy metals or any substance established to cause altered consciousness.…”

Section: Subjectsmentioning

confidence: 99%

Peripheral T-lymphocyte and natural killer cell population imbalance is associated with septic encephalopathy in patients with severe sepsis

Qiu

Tong

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Septic encephalopathy (SE) is a diffuse cerebral dysfunction resulting from a systemic inflammatory response, and is associated with an increased risk of mortality. The pathogenesis of SE is complex and multifactorial, but unregulated immune imbalance may be an important factor. The current retrospective study examined the clinical data of 86 patients with severe sepsis who were admitted to the Intensive Care Unit at Zhongshan Hospital, Xiamen University (Xiamen, China) from January, 2014 to January, 2015. The patients were assigned to SE and non-SE patient groups according to the presence or absence of SE. The proportion of T-lymphocyte subsets and natural killer (NK) cells in the immune cell population, representing the function of the immune system, were analyzed for their association with SE and compared with other clinical predictors and biomarkers. + T-lymphocytes were demonstrated to be independently associated with SE (respectively, P=0. 012 and OR, 4.763; P=0.005 and OR, 0.810). An area under the curve analysis of a receiver operating characteristic curve of the two indicators revealed that these were equally powerful measures in prediction of SE (Z=1.247, P>0.05). The present results confirm that SE leads to higher mortality in patients with severe sepsis, and demonstrate that immune imbalance is important in the development of SE. The proportion of CD4 + T-lymphocytes present were revealed in the current study to be a powerful predictor of SE in patients with severe sepsis.

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Septic encephalopathy: does inflammation drive the brain crazy?

Cited by 70 publications

References 114 publications

Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy

Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy

In Vivo Imaging of Septic Encephalopathy

Peripheral T-lymphocyte and natural killer cell population imbalance is associated with septic encephalopathy in patients with severe sepsis

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