title: Clematichinenoside protects blood brain barrier against ischemic stroke superimposed on systemic inflammatory challenges through up-regulating A20.
abstract: Suppression of excessive inflammation can ameliorate blood brain barrier (BBB) injury, which shows therapeutic potential for clinical treatment of brain injury induced by stroke superimposed on systemic inflammatory diseases. In this study, we investigated whether and how clematichinenoside (AR), an anti-inflammatory triterpene saponin, protects brain injury from stroke superimposed on systemic inflammation. Lipopolysaccharide (LPS) was intraperitoneally injected immediately after middle cerebral artery occlusion (MCAO) in rats. Rat microvessel endothelial cells (rBMECs) were exposed to hypoxia/reoxygenation (H/R) coexisting with LPS. The results revealed that AR suppressed the excessive inflammation, restored BBB dysfunction, alleviated brain edema, decreased neutrophil infiltration, lessened neurological dysfunction, and decreased infarct rate. Further study demonstrated that the expression of nucleus nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) were suppressed by AR via zinc finger protein A20. Besides, AR increased in vitro BBB integrity through A20. In conclusion, AR alleviated cerebral inflammatory injury through A20-NF-κB signal pathway, offering an alternative medication for stroke associated with systemic inflammatory diseases.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Han
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Nandani Darshika
authors.initials: ND
authors.lastname: Kodithuwakku
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Sha
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Wenhuan
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Pharmacognosy and the Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, 210009, PR China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Fengwen
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: yunmanlicpu@hotmail.com.
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000517:prevention & control*; D015687:Cell Hypoxia / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000648:ultrastructure; D020556:Neutrophil Infiltration / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000008:administration & dosage*; D020521:Stroke / Q000517:prevention & control*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012503:Saponins; D014409:Tumor Necrosis Factor-alpha; C581539:clematichinenoside; C000602677:TNFAIP3 protein, rat; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: Blood brain barrier; Clematichinenoside; Ischemic stroke; NF-κB; Systemic inflammation; Zinc finger protein A20