Anti-inflammatory activity of 21(alpha, beta)-methylmelianodiols, novel compounds from Poncirus trifoliata Rafinesque.
The fruits of Poncirus trifoliata (L.) are widely used in Oriental medicine as a remedy for allergic inflammation. As a part of our program to screen medicinal plants for potential anti-inflammatory compounds, 21alpha-methylmelianodiol (21alpha-MMD) and 21beta-methylmelianodiol (21beta-MMD), which are two isomers of 21-methylmelianodiol isolated from the fruits of P. trifoliata for the first time, were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. 21alpha-MMD and 21beta-MMD attenuated LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expressions as well as the mRNA levels of iNOS, COX-2, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). To investigate the mechanism involved, we examined the effect of 21alpha-MMD and 21beta-MMD on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. Both 21alpha-MMD and 21beta-MMD significantly inhibited LPS-induced NF-kappaB transcriptional activity in RAW 264.7 macrophages. Moreover, the in vivo anti-inflammatory effect of 21alpha-MMD was examined in two mouse models of acute inflammation. In the carrageenan-induced paw edema model, administration of 21alpha-MMD (20 and 100 mg/kg, i.p.) dose-dependently reduced paw swelling. In addition, 21alpha-MMD significantly inhibited the dye leakage in an acetic acid-induced vascular permeability assay. Taken together, our data indicate that 21-methylmelianodiol is an important constituent of the fruit of P. trifoliata, and that the inhibition of iNOS and COX-2 expression by 21alpha-MMD and 21beta-MMD might be one of the mechanisms responsible for their anti-inflammatory effects.
Zhou
Hong Yu
HY
Natural Products Research Institute, College of Pharmacy, Seoul National University, 28 Yeonkun-Dong, Jongno-Ku Seoul 110-460, South Korea.
Shin
Eun Myung
EM
Guo
Lian Yu
LY
Zou
Li Bo
LB
Xu
Guang Hua
GH
Lee
Seung-Ho
SH
Ze
Keum Ryon
KR
Kim
Eun-Kyung
EK
Kang
Sam Sik
SS
Kim
Yeong Shik
YS
D019342:Acetic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002351:Carrageenan; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D032104:Poncirus; D012333:RNA, Messenger / Q000096:biosynthesis; D013237:Stereoisomerism; D014158:Transcription, Genetic; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
C525645:21-methylmelianodiol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014315:Triterpenes; D009569:Nitric Oxide; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D019342:Acetic Acid