title: Astragaloside IV inhibits microglia activation via glucocorticoid receptor mediated signaling pathway.
abstract: Inhibition of microglia activation may provide therapeutic treatment for many neurodegenerative diseases. Astragaloside IV (ASI) with anti-inflammatory properties has been tested as a therapeutic drug in clinical trials of China. However, the mechanism of ASI inhibiting neuroinflammation is unknown. In this study, we showed that ASI inhibited microglia activation both in vivo and in vitro. It could enhance glucocorticoid receptor (GR)-luciferase activity and facilitate GR nuclear translocation in microglial cells. Molecular docking and TR-FRET GR competitive binding experiments demonstrated that ASI could bind to GR in spite of relative low affinity. Meanwhile, ASI modulated GR-mediated signaling pathway, including dephosphorylation of PI3K, Akt, I κB and NF κB, therefore, decreased downstream production of proinflammatory mediators. Suppression of microglial BV-2 activation by ASI was abrogated by GR inhibitor, RU486 or GR siRNA. Similarly, RU486 counteracted the alleviative effect of ASI on microgliosis and neuronal injury in vivo. Our findings demonstrated that ASI inhibited microglia activation at least partially by activating the glucocorticoid pathway, suggesting its possible therapeutic potential for neuroinflammation in neurological diseases.
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Hong-Shuai
authors.initials: HS
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Hai-Lian
authors.initials: HL
authors.lastname: Shi
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, Hamilton, Montana, 59840, USA.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Peterson
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Yun-Yi
authors.initials: YY
authors.lastname: Lan
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: He
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, Hamilton, Montana, 59840, USA.
authors.forename: Tyson
authors.initials: T
authors.lastname: Woods
authors.affiliation: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200030, China.
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Zheng-Tao
authors.initials: ZT
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D012503:Saponins / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012503:Saponins; D051193:Toll-Like Receptors; D014315:Triterpenes; C052064:astragaloside A