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ISSN (Online): 1873-5592

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Review Article

Sepsis-Associated Brain Dysfunction: Mechanisms, Clinical Insights, and Therapeutic Strategies

Author(s): Nazrana Payal, Juhi Saxena, Vijay Kumar Srivastava, Sanket Kaushik, Arif Jamal Siddiqui, Kartik Chauhan, Aditi Sharma, Anupam Jyoti* and Lalit Sharma*

Volume 26, Issue 14, 2025

Published on: 02 September, 2025

Page: [992 - 1009] Pages: 18

DOI: 10.2174/0113894501381183250825144834

Price: $65

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Abstract

Sepsis is a lethal clinical condition representing severe inflammation and immune suppression to pathogen or infection, leading to tissue damage or organ dysfunction. Hyper-inflammation and immune suppression cause a fatal, escalated Blood-Brain Barrier permeability, being a secondary response towards infection resulting in sepsis-associated brain dysfunction. These changes in the BBB lead to the brain’s susceptibility to increased morbidity and mortality. An important mechanism of sepsis-associated brain dysfunction includes excessive activation of microglial cells, altered brain endothelial barrier function, and BBB dysfunction. Lipopolysaccharide, a bacterial cell wall component (endotoxin), by forming a complex through membrane- bound CD receptors on macrophages, monocytes, and neutrophils, begins synthesizing anti- inflammatory agents for defense of the host, including nitric oxide, cytokines, chemokines, interleukins, and the complement system. Unrestrained endotoxemia and pro-inflammatory cytokines result in microglial as well as brain endothelial cell stimulation, downregulation of tight junctions, along with intense recruitment of leucocytes. Subsequent neuroinflammation, together with BBB dysfunction, aggravates brain pathology as well as worsens sepsis-associated brain dysfunction. The clinical demonstration includes mild (confusion and delirium) along with severe (cognitive impairment, coma, as well as sequel death). Different clinical neurophysiological evaluation parameters can be used for the quantification and important issues of the disorder, including SOFA, imaging methods, and the use of biomarkers associated with brain dysfunction. The present review addresses the mechanism, clinical examination, the long-term cognitive effects, and current treatment modalities for sepsis-associated brain dysfunction.

Keywords: Sepsis-associated brain dysfunction, blood brain barrier, brain endothelial cells, bacterial cell wall, endotoxin, anti-inflammation.

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Graphical Abstract

Graphical abstract illustrating key findings of the study

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