title: 2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke.
abstract: 2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10-100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.
authors.affiliation: Stroke and Neurovascular Disease Center, Section of Cerebrovascular Disease, Department of Neurology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chang-Ming
authors.initials: CM
authors.lastname: Chern
authors.affiliation: National Taipei University of Nursing and Health Science, Taiwan.
authors.forename: Yea-Hwey
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Martial Arts, Chinese Culture University, Taipei, Taiwan.
authors.forename: Kuo-Tong
authors.initials: KT
authors.lastname: Liou
authors.affiliation: Department of Chinese Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan; Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan.
authors.forename: Yu-Chang
authors.initials: YC
authors.lastname: Hou
authors.affiliation: Department of Biotechnology, College of Medicine and Nursing, Hung-Kuang University, Taichung, Taiwan.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, College of Life Science, National Chung-Hsing University, Taichung, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; National Taipei University of Nursing and Health Science, Taiwan. Electronic address: yuhcs@nricm.edu.tw.
authors.forename: Yuh-Chiang
authors.initials: YC
authors.lastname: Shen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D000089662:Doublecortin Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D055495:Neurogenesis / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020521:Stroke / Q000188:drug therapy*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: C447630:2-Methoxystypandrone; D039481:CD11b Antigen; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D007155:Immunologic Factors; D009285:Naphthoquinones; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2
keywords: 2-MS; 2-Methoxystypandrone (2MS); 2-methoxystypandrone; B-cell lymphoma 2; BBB; Bcl-2; COX-2; DCX; GSK3; Glycogen synthase kinase 3 (GSK3); I/R; Ischemic stroke; MCAO; NF-κB; SGZ; SVZ; Subgranular zone (SGZ); blood–brain barrier; cyclooxygenase-2; doublecortin; glycogen synthase kinase 3; iNOS; inducible nitric oxide synthase; ischemia reperfusion; middle cerebral artery occlusion/reperfusion; nuclear factor-kappa B; subgranular zone; subventricular zone; β-Catenin