title: Astragaloside IV attenuates experimental autoimmune encephalomyelitis of mice by counteracting oxidative stress at multiple levels.
abstract: Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China ; Department of Pharmacognosy, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: He
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Hongshuai
authors.initials: H
authors.lastname: Liu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004365:Drugs, Chinese Herbal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D020825:T-Box Domain Proteins / Q000235:genetics; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000098815:T-bet Transcription Factor
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D039481:CD11b Antigen; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012503:Saponins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014315:Triterpenes; C528900:glial fibrillary astrocytic protein, mouse; C052064:astragaloside A; D052247:Nitric Oxide Synthase Type II