Academic Journal
Aspirin mitigates sepsis-associated encephalopathy by modulating ICAM-1 and MMP-9 signaling: Evidence from clinical cohorts and mechanistic experiments.
| Τίτλος: | Aspirin mitigates sepsis-associated encephalopathy by modulating ICAM-1 and MMP-9 signaling: Evidence from clinical cohorts and mechanistic experiments. |
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| Συγγραφείς: | Cui Y; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; School of Nursing and Rehabilitation, Shandong University, Jinan, Shandong, China; Innovation Research Center for Sepsis and Multiple Organ Injury, Shandong University, Jinan, Shandong, China., Lu S; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; Interdisciplinary Center, Shandong University, Jinan, Shandong, China., Lv K; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China., Zhang H; Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; NHC Key Lab of Health Economics and Policy Research, Shandong University, Jinan, Shandong, China., Pang M; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; School of Nursing and Rehabilitation, Shandong University, Jinan, Shandong, China., Wang H; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; School of Nursing and Rehabilitation, Shandong University, Jinan, Shandong, China., Tian X; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; School of Nursing and Rehabilitation, Shandong University, Jinan, Shandong, China., Chen H; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China., Qiu J; Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: qiujihua@sdu.edu.cn., Wang H; Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China; School of Nursing and Rehabilitation, Shandong University, Jinan, Shandong, China. Electronic address: wanghao34@126.com. |
| Πηγή: | Experimental neurology [Exp Neurol] 2026 Sep; Vol. 403, pp. 115813. Date of Electronic Publication: 2026 May 10. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Orlando Fl : Academic Press Original Publication: New York. |
| Ιατρικοί όροι (MeSH): | Matrix Metalloproteinase 9*/metabolism , Sepsis-Associated Encephalopathy*/metabolism , Sepsis-Associated Encephalopathy*/drug therapy , Sepsis-Associated Encephalopathy*/prevention & control , Intercellular Adhesion Molecule-1*/metabolism , Intercellular Adhesion Molecule-1*/drug effects , Aspirin*/therapeutic use , Aspirin*/pharmacology , Signal Transduction*/drug effects , Anti-Inflammatory Agents, Non-Steroidal*/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal*/pharmacology, Hippocampus/metabolism ; Hippocampus/drug effects ; Animals ; Mice ; Humans ; Male ; Mice, Inbred C57BL |
| Περίληψη: | Sepsis-associated encephalopathy (SAE) is a devastating complication contributing substantially to intensive care unit mortality and long-term cognitive impairment. Although observational studies suggest that aspirin use was associated with reduced sepsis-related mortality, its neuroprotective potential against SAE and underlying molecular mechanisms remain unclear. Using data from the Medical Information Mart for Intensive Care IV and eICU Collaborative Research Database, we demonstrated through propensity score matching and inverse probability of treatment weighting that aspirin use was significantly associated with reduced SAE incidence without increased gastrointestinal bleeding risk. Meta-analysis yielded a pooled protective association (OR 0.69, 95% CI 0.57-0.83) with moderate heterogeneity (I2 = 63.6%). Transcriptomic profiling of hippocampal tissues from lipopolysaccharide (LPS)-induced SAE mice revealed intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) as aspirin-responsive hub genes enriched in leukocyte adhesion and extracellular matrix remodeling pathways. In murine models, aspirin significantly improved cognitive performance in novel object recognition and Y-maze tests, while reducing anxiety-like behavior. Mechanistically, aspirin suppressed LPS-induced upregulation of ICAM-1 and MMP-9 expression in hippocampus and prefrontal cortex, preserved blood-brain barrier integrity by restoring tight junction-related and adherens junction-related proteins reducing Evans blue extravasation, attenuated neuroinflammatory signaling through decreased cyclooxygenase-2, nuclear factor-κB, tumor necrosis factor-α, interleukin-6, and prostaglandin E2 expression, and reduced cleaved caspase-3-mediated neuronal apoptosis. These findings provide convergent evidence that aspirin mitigates SAE through suppression of ICAM-1 and MMP-9-associated inflammatory and endothelial dysfunction, supporting its potential as a neuroprotective adjunctive therapy and identifying ICAM-1 and MMP-9 as promising therapeutic targets for SAE. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no competing interests. |
| Σχόλια: | Erratum in: Exp Neurol. 2026 Sep;403:115843. doi: 10.1016/j.expneurol.2026.115843.. (PMID: 42203555) |
| Contributed Indexing: | Keywords: Aspirin; Blood-brain barrier; ICAM-1; MMP-9; Sepsis-associated encephalopathy |
| Substance Nomenclature: | EC 3.4.24.35 (Matrix Metalloproteinase 9) 126547-89-5 (Intercellular Adhesion Molecule-1) R16CO5Y76E (Aspirin) 0 (Anti-Inflammatory Agents, Non-Steroidal) EC 3.4.24.35 (Mmp9 protein, mouse) |
| Entry Date(s): | Date Created: 20260512 Date Completed: 20260612 Latest Revision: 20260922 |
| Update Code: | 20260922 |
| DOI: | 10.1016/j.expneurol.2026.115813 |
| PMID: | 42119687 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2430 |
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| DOI: | 10.1016/j.expneurol.2026.115813 |