Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies

Abstract

Sepsis is an organ dysfunction caused by an uncontrolled inflammatory response from the host to an infection. Sepsis is the main cause of morbidity and mortality in intensive care units (ICU) worldwide. One of the first organs to suffer from injuries resulting from sepsis is the brain. The central nervous system (CNS) is particularly vulnerable to damage, mediated by inflammatory and oxidative processes, which can cause the sepsis-associated encephalopathy (SAE), being reported in up to 70% of septic patients. This review aims to bring a summary of the main pathophysiological changes and dysfunctions in SAE, and the main focuses of current experimental studies for new treatments and therapies. The pathophysiology of SAE is complex and multifactorial, combining intertwined processes, and is promoted by countless alterations and dysfunctions resulting from sepsis, such as inflammation, neuroinflammation, oxidative stress, reduced brain metabolism, and injuries to the integrity of the blood-brain barrier (BBB). The treatment is limited once its cause is not completely understood. The patient's sedation is far to provide an adequate treatment to this complex condition. Studies and experimental advances are important for a better understanding of its pathophysiology and for the development of new treatments, medicines, and therapies for the treatment of SAE and to reduce its effects during and after sepsis. Keywords Sepsis . Encephalopathy . Experimental studies . Brain Abbreviations SAE Sepsis-associated encephalopathy ICU Intensive care units CNS Central nervous system BBB Blood-brain barrier TNF-α Necrosis factor alpha IL Interleukins CSF Cerebrospinal fluid ROS Reactive oxygen species NO Nitric oxide RNS Reactive nitrogen species H 2 O 2 Hydrogen peroxide O 2 .

NU9056, a KAT 5 Inhibitor, Treatment Alleviates Brain Dysfunction by Inhibiting NLRP3 Inflammasome Activation, Affecting Gut Microbiota, and Derived Metabolites in LPS-Treated Mice

“…BBB damage was involved in the occurrence and development of many neuroinflammatory diseases, including SAE. Therefore, many therapeutic drugs related to neurological diseases have the effect of protecting BBB ( 29 ). Our research revealed that NU9056 could alleviate the BBB damage of LPS-induced mice.…”

The Improvement of Sepsis-Associated Encephalopathy by P2X7R Inhibitor through Inhibiting the Omi/HtrA2 Apoptotic Signaling Pathway

“…When Omi/HtrA2 enters the cytoplasm from mitochondria, XIAP will be degraded, thus, inhibiting the degradation of caspase-9 by XIAP [ 27 – 29 ], and increased expression of caspase-9 activates caspase-3, ultimately causing intracellular DNA damage. It has been proved that cell apoptosis induced by external damaging stimuli is significantly reduced after mitochondrial serine protease Omi/HtrA2 is knocked down [ 30 ]. Therefore, the effect of P2X7R activation on XIAP and caspase-3-related apoptosis needs further exploration.…”

Emerging Trends and Hot Spots in Sepsis-Associated Encephalopathy Research From 2001 to 2021: A Bibliometric Analysis

“…The severity of SAE can range from delirium to coma. Disturbance of consciousness is an early warning sign of developing sepsis in a majority of cases (1)(2)(3)(4)(5). At present, SAE was reported by some studies to have an incidence of as high as 42% (6), with a higher case fatality rate of 28-180 days, compared with that of non-SAE.…”