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Citations to this article

Circulating heparan sulfate fragments mediate septic cognitive dysfunction
Joseph A. Hippensteel, … , Paco S. Herson, Eric P. Schmidt
Joseph A. Hippensteel, … , Paco S. Herson, Eric P. Schmidt
Published February 5, 2019
Citation Information: J Clin Invest. 2019;129(4):1779-1784. https://doi.org/10.1172/JCI124485.
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Concise Communication Neuroscience Article has an altmetric score of 20

Circulating heparan sulfate fragments mediate septic cognitive dysfunction

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Abstract

Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor–mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that the avidity of heparan sulfate for BDNF increased with sulfation at the 2-O position of iduronic acid and the N position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O– and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O– and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.

Authors

Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, Eric P. Schmidt

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 Total
Citations: 6 6 13 12 19 15 5 76
Citation information
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Citations to this article in year 2023 (13)

Title and authors Publication Year
Lung infection by P. aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice
Villalba N, Ma Y, Gahan SA, Joly-Amado A, Spence S, Yang X, Nash K, Yuan SY
Research square 2023
Using heparan sulfate octadecasaccharide (18-mer) as a multi-target agent to protect against sepsis
Liao YE, Xu Y, Arnold K, Zhang F, Li J, Sellers R, Yin C, Pagadala V, Inman AM, Linhardt RJ, Xu D, Pawlinski R, Liu J
Proceedings of the National Academy of Sciences 2023
Endothelial glycocalyx-associated molecules as potential serological markers for sepsis-associated encephalopathy: A systematic review and meta-analysis
Baby S, Reljic T, Villalba N, Kumar A, Yuan SY
PloS one 2023
Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment
Hogwood J, Gray E, Mulloy B
Pharmaceuticals 2023
Heparan sulfates and heparan sulfate binding proteins in sepsis
Liao YE, Liu J, Arnold K
Frontiers in Molecular Biosciences 2023
Dysfunction of NRG1/ErbB4 Signaling in the Hippocampus Might Mediate Long-term Memory Decline After Systemic Inflammation.
Gao YZ, Wu XM, Zhou ZQ, Liu PM, Yang JJ, Ji MH
Molecular Neurobiology 2023
Corticosterone enhances formation of non-fear but not fear memory during infectious illness
Hill A, Johnston C, Agranoff I, Gavade S, Spencer-Segal J
Frontiers in behavioral neuroscience 2023
Lung infection by Pseudomonas aeruginosa induces neuroinflammation and blood–brain barrier dysfunction in mice
Villalba N, Ma Y, Gahan SA, Joly-Amado A, Spence S, Yang X, Nash KR, Yuan SY
Journal of Neuroinflammation 2023
In Vivo Profiling of the Vascular Cell Surface Proteome in Murine Models of Bacteremia.
Spliid C, Esko JD, Malmström J, Toledo AG
Methods in molecular biology (Clifton, N.J.) 2023
Organotypic heterogeneity in microvascular endothelial cell responses in sepsis—a molecular treasure trove and pharmacological Gordian knot
Cleuren A, Molema G
Frontiers in Medicine 2023
Endothelial Glycocalyx Degradation Patterns in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome: A Single Center Retrospective Observational Study
Sallee CJ, Hippensteel JA, Miller KR, Oshima K, Pham AT, Richter RP, Belperio J, Sierra YL, Schwingshackl A, Mourani PM, Schmidt EP, Sapru A, Maddux AB
Journal of Intensive Care Medicine 2023
A role for decorin in improving motor deficits after traumatic brain injury
Oshima K, Siddiqui N, Orfila JE, Carter D, Laing J, Han X, Zakharevich I, Iozzo RV, Ghasabayan A, Moore H, Zhang F, Linhardt RJ, Moore EE, Quillinan N, Schmidt EP, Herson PS, Hippensteel JA
Matrix biology : journal of the International Society for Matrix Biology 2023
Lung endothelium, tau, and amyloids in health and disease
Balczon R, Lin MT, Voth S, Nelson AR, Schupp JC, Wagener BM, Pittet JF, Stevens T
Physiological reviews 2023

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