Parthenolide was found to inhibit activation of transcription factor nuclear factor

Investigations of the anti-inflammatory properties of parthenolide, and feverfew have focused on suppression of primary inflammatory endpoints such as platelet aggregation [1] and carrageenan-induced mouse [2] and rat [3] paw edema. Additional studies have evaluated parthenolide’s inhibitory effect on inflammatory mediators including activity and expression of cyclooxygenase (COX) [4,5], generation of prostaglandins [6,7], and leukotrienes (LT) [4] and expression of proinflammatory cytokines [5,8]. Most recently, the compound was found to inhibit activation of transcription factor nuclear factor (NF)-?B [9-12]. Parthenolide, a major sesquiterpene lactone present in extracts of the herb Feverfew, has been investigated for its inhibitory effects on mediators of inflammation, including the proinflammatory cytokines. Although parthenolide’s anti-inflammatory effects have been investigated in vitro, little in vivo data are available. Moreover, the molecular mechanisms for these inhibitory effects are not fully understood. The objective of this study was to test the hypothesis that parthenolide suppresses lipopolysaccharide (LPS)-induced serum (interleukin) IL-6, tumor necrosis factor (TNF)-?, IL-1? and cyclooxygenase (COX)-2 expression in mice as indicated by reduced splenic and liver mRNA levels [13]. References: 1. Groenewegen WA, Heptinstall S: A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol 1990, 42:553-557. 2. Schinella GR, Giner RM, Recio MC, Mordujovich dB, Rios JL, Manez S: Anti-inflammatory effects of South American Tanacetum vulgare. J Pharm Pharmacol 1998, 50:1069-1074. 3. Jain NK, Kulkarni SK: Antinociceptive and anti-inflammatory effects of Tanacetum parthenium L. extract in mice and rats. J Ethnopharmacol 1999, 68:251-259. 4. Sumner H, Salan U, Knight DW, Hoult JR: Inhibition of 5-lipoxygenase and cyclooxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. Biochem Pharmacol 1992, 43:2313-2320. 5. Hwang D, Fischer NH, Jang BC, Tak H, Kim JK, Lee W: Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases. Biochem Biophys Res Commun 1996, 226:810-8. 6. O’Neill LA, Barrett ML, Lewis GP: Extracts of feverfew inhibit mitogen-induced human peripheral blood mononuclear cell proliferation and cytokine mediated responses: a cytotoxic effect. Br J Clin Pharmacol 1987, 23:81-83. 7. Pugh WJ, Sambo K: Prostaglandin synthetase inhibitors in feverfew. J Pharm Pharmacol 1988, 40:743-745. 8. Uchi H, Arrighi JF, Aubry JP, Furue M, Hauser C: The sesquiterpene lactone parthenolide inhibits LPS- but not TNF-alpha-induced maturation of human monocyte-derived dendritic cells by inhibition of the p38 mitogen-activated protein kinase pathway. J Allergy Clin Immunol 2002, 110:269-276. 9. Hehner SP, Hofmann TG, Droge W, Schmitz ML: The antiinflammatory sesquiterpene lactone parthenolide inhibits NF- kappa B by targeting the I kappa B kinase complex. J Immunol 1999, 163:5617-23. 10. Hehner SP, Heinrich M, Bork PM, Vogt M, Ratter F, Lehmann V, et al.: Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation

of I kappa B-alpha and I kappa B-beta. J Biol Chem 1998, 273:1288-1297. 11. Bork PM, Schmitz ML, Kuhnt M, Escher C, Heinrich M: Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-kappaB. FEBS Lett 1997, 402:85-90. 12. Rungeler P, Castro V, Mora G, Goren N, Vichnewski W, Pahl HL: Inhibition of transcription factor NF-kappaB by sesquiterpene lactones: a proposed molecular mechanism of action. Bioorg Med Chem 1999, 7:2343-2352. 13. Smolinski AT, Pestka JJ. Comparative effects of the herbal constituent parthenolide (Feverfew) on lipopolysaccharide-induced inflammatory gene expression in murine spleen and liver. Journal of Inflammation 2005, 2:6 doi:10.1186/1476-9255-2-6