title: Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia.
abstract: By using two structurally unrelated hydrogen sulfide (H2 S) donors 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione (ADT) and sodium hydrosulfide (NaHS), this study investigated if H2 S protected blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO). ICR mice underwent MCAO and received H2 S donors at 3 h after reperfusion. Infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression were examined at 48 h after MCAO. We also investigated if ADT protected BBB integrity by suppressing post-ischemic inflammation-induced Matrix Metalloproteimase-9 (MMP9) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). ADT increased blood H2 S concentrations, decreased infarction, and improved neurological deficits. Particularly, ADT reduced EB extravasation, brain edema and preserved expression of tight junction proteins in the ischemic brain. NaHS also increased blood H2 S levels and reduced EB extravasation following MCAO. Moreover, ADT inhibited expression of pro-inflammatory markers induced Nitric Oxide Synthase (iNOS) and IL-1β while enhanced expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Accordingly, ADT attenuated ischemia-induced expression and activity of MMP9. Moreover, ADT reduced NOX-4 mRNA expression, NOX activity, and inhibited nuclear translocation of Nuclear Factor Kappa-B (NF-κB) in the ischemic brain. In conclusion, H2 S donors protected BBB integrity following experimental stroke possibly by acting through NF-κB inhibition to suppress neuroinflammation induction of MMP9 and NOX4-derived free radicals. To determine H2 S effects on blood-brain barrier (BBB) disruption following stroke, we used two structurally unrelated H2 S donors ADT and NaHS. Both ADT and NaHS remarkably protected BBB integrity following experimental stroke. The slow-releasing donor ADT also reduced post-ischemic inflammation-induced expression and activity of MMP9 and NOX4 in the ischemic brain possibly by inhibiting NF-κB activation.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China; The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Wang
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Guizhen
authors.initials: G
authors.lastname: Ao
authors.forename: Lifang
authors.initials: L
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Huaping
authors.initials: H
authors.lastname: Du
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001929:Brain Edema / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D004396:Coloring Agents; D004797:Enzyme-Linked Immunosorbent Assay; D005070:Evans Blue; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000097:blood / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents; D009195:Peroxidase / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013871:Thiones / Q000494:pharmacology*
chemical_list: C000597608:5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione; D004396:Coloring Agents; D006573:Heterocyclic Compounds, 1-Ring; D016328:NF-kappa B; D018696:Neuroprotective Agents; D013871:Thiones; D016753:Interleukin-10; D005070:Evans Blue; D009195:Peroxidase; D019255:NADPH Oxidases; D006862:Hydrogen Sulfide
keywords: Blood-brain barrier; cerebral ischemia; hydrogen sulfide; vasoprotection