Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells.
Evodia rutaecarpa is commonly used as an anti-inflammatory drug in traditional Chinese medicine. We previously identified four bioactive compounds (dehydroevodiamine (I), evodiamine (II), rutaecarpine (III), and synephrine (IV)) from the ethanol extract of E. rutaecarpa, but their effects and mechanism(s) of action remain unclear. To study the anti-inflammatory potential and the possible underlying mechanism(s), their effects on phorbol-12-myristate-13-acetate (PMA)- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced reactive oxygen species production in neutrophils was studied, as well as lipopolysaccharide (LPS)-induced nitric oxide (NO) production and inducible NO synthetase (iNOS) expression in microglial cells. The ethanol extract of E. rutaecarpa displayed potent antioxidative effects against both PMA- and fMLP-induced reactive oxygen species production in neutrophils (with IC50 values of around 2.7-3.3 microg/ml). Although less potent than the ethanol extract of E. rutaecarpa, compounds I-IV all concentration-dependently inhibited PMA- and fMLP-induced reactive oxygen species production, with compound IV consistently being the most potent agent among these active components. The antioxidative effects of the ethanol extract of E. rutaecarpa and these compounds were partially due to inhibition (10%-33%) of NADPH oxidase activity, a predominant reactive oxygen species-producing enzyme in neutrophils, and to a minor extent to their direct radical-scavenging properties. The ethanol extract of E. rutaecarpa also inhibited LPS-induced NO production (with an IC50 of around 0.8 microg/ml) and iNOS upregulation in microglial cells that was partially mimicked by compounds I, II, and III, but not compound IV. Our results suggest that the ethanol extract of E. rutaecarpa and its four bioactive components all exhibited anti-inflammatory activities which could be partially explained by their different potentials for inhibiting NADPH oxidase-dependent reactive oxygen species and/or iNOS-dependent NO production in activated inflammatory cells.
Ko
Han-Chieh
HC
National Research Institute of Chinese Medicine, Taiwan.
Wang
Yea-Hwey
YH
Liou
Kuo-Tong
KT
Chen
Chi-Ming
CM
Chen
Chih-Hsiang
CH
Wang
Wen-Yen
WY
Chang
Shiou
S
Hou
Yu-Chang
YC
Chen
Kuo-Tung
KT
Chen
Chieh-Fu
CF
Shen
Yuh-Chiang
YC
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002460:Cell Line; D000431:Ethanol / Q000737:chemistry; D032086:Evodia / Q000737:chemistry*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010851:Picrates; D010936:Plant Extracts / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013578:Synephrine / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D052999:Quinazolinones
D000470:Alkaloids; D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D000431:Ethanol; D006834:Hydrazines; D026121:Indole Alkaloids; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010851:Picrates; D010936:Plant Extracts; D011799:Quinazolines; D017382:Reactive Oxygen Species; D013578:Synephrine; D013755:Tetradecanoylphorbol Acetate; C016658:phorbolol myristate acetate; C028633:dehydroevodiamine; C028632:rutecarpine; D052999:Quinazolinones; C049639:evodiamine; C004931:1,1-diphenyl-2-picrylhydrazyl; C496317:Nos2 protein, mouse