title: Attenuated Blood-Brain Barrier Dysfunction by XQ-1H Following Ischemic Stroke in Hyperlipidemic Rats.
abstract: Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion (MCAO) modeled ischemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlipidemic condition. Additionally, lipopolysaccharide (LPS) incubation with rat brain microvessel endothelial cells (rBMECs) was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, downregulated MMP-9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory response in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-κB inflammatory signal and downstream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Fang
authors.forename: Lan
authors.initials: L
authors.lastname: Sha
authors.forename: Nandani Darshika
authors.initials: ND
authors.lastname: Kodithuwakku
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Han
authors.forename: Lishun
authors.initials: L
authors.lastname: Mao
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001929:Brain Edema / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D046934:Ginkgolides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D055806:Microvessels / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010539:Permeability; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D046934:Ginkgolides; D018836:Inflammation Mediators; D007783:Lactones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013451:Sulfonic Acids; D019010:Vascular Cell Adhesion Molecule-1; C544311:XQ-1H compound; D002784:Cholesterol; D020780:Matrix Metalloproteinase 9; D010100:Oxygen