title: Isolation and identification of anti-inflammatory constituents from Ligusticum chuanxiong and their underlying mechanisms of action on microglia.
abstract: Stroke is the third most common cause of death worldwide. Recent findings showed that the severity of cerebrovascular diseases including ischemic stroke correlates with inflammation mediated responses in the neural cells. During ischemia, inflammatory mediators including tumor necrosis factor-alpha (TNF-α) and nitric oxide are produced by microglia, which play a central role in the pathogenesis of the disease. Ligusticum chuanxiong (LCX) is a commonly used traditional Chinese medicine (TCM) for empiric treatment of cerebrovascular and cardiovascular diseases for many centuries. By applying a bioactivity-guided fractionation scheme, two compounds with inhibition on neuroinflammation were isolated from LCX. Using chromatographic and spectrometric methods, they were identified to be senkyunolide A and Z-ligustilide. They could inhibit the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells and human peripheral blood monocyte derived macrophages. In addition, both compounds protected Neuro-2a cells from neuroinflammatory toxicity induced by the conditioned culture media produced by LPS-stimulated BV-2 cells. The underlying mechanisms of action of senkyunolide A were further delineated. Its inhibitory effects were shown to be independent of the phosphorylation of mitogen-activated protein kinases (MAPK) and translocation of nuclear factor kappa B (NF-κB). However, senkyunolide A could increase the degradation of TNF-α mRNA and reduce its half life by 43%. In conclusion, bioactivity-guided fractionation is an effective way of isolating bioactive compounds from medicinal herbs. In addition, senkyunolide A and Z-ligustilide isolated from LCX may be considered as potential complementary drug candidates for treating inflammatory processes associated with cerebrovascular diseases.
authors.affiliation: Molecular Chinese Medicine Laboratory, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. terryor@graduate.hku.hk
authors.forename: Terry C T
authors.initials: TC
authors.lastname: Or
authors.forename: Cindy L H
authors.initials: CL
authors.lastname: Yang
authors.forename: Anna H Y
authors.initials: AH
authors.lastname: Law
authors.forename: James C B
authors.initials: JC
authors.lastname: Li
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001681:Biological Assay / Q000379:methods; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D006801:Humans; D030004:Ligusticum; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001572:Benzofurans; D004365:Drugs, Chinese Herbal; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C027820:ligustilide; C045855:3-N-butyl-4,5-dihydrophthalide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D015107:4-Butyrolactone; C101574:chuangxiong extract