The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase.
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BACKGROUND: Biologically active natural products continue to be useful in the exploration and control of intracellular signaling processes. For example, the sesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium) appears to inhibit the pro-inflammatory signaling pathway. Parthenolide's direct molecular target, however, remains unknown. We set out to identify the molecular mechanisms of parthenolide's anti-inflammatory activity. RESULTS: A parthenolide affinity reagent was synthesized and shown to bind directly to and inhibit IkappaB kinase beta (IKKbeta), the kinase subunit known to play a critical role in cytokine-mediated signaling. Mutation of cysteine 179 in the activation loop of IKKbeta abolished sensitivity towards parthenolide. Moreover, we showed that parthenolide's in vitro and in vivo anti-inflammatory activity is mediated through the alpha-methylene gamma-lactone moiety shared by other sesquiterpene lactones. CONCLUSIONS: In recent years, the multi-subunit IKK complex has been shown to be responsible for cytokine-mediated stimulation of genes involved in inflammation and as such represents an attractive target for pharmaceutical intervention. Our finding that parthenolide targets this kinase complex provides a possible molecular basis for the anti-inflammatory properties of parthenolide. In addition, these results may be useful in the development of additional anti-inflammatory agents. (+info)
5-Hydroxytryptamine-inhibiting property of Feverfew: role of parthenolide content.
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AIM: To study the mechanism of antimigraine activity of Tanacetum parthenium (Feverfew), its extracts and parthenolide, a component of Feverfew, by observing their effect on 5-HT storage and release, and stimulation of 5-HT2B and 5-HT2A receptors. Also to standardize a dosage form of Feverfew with respect to its parthenolide content. METHODS: Isometric responses to 5-HT and an indirect acting serotonergic, d-fenfluramine, were obtained on rat fundus and ileum. In one set of experiments the effect of dichloromethane extract of Feverfew and parthenolide was observed on the above. The extract was then thermally degraded upto 10%, 23%, and 33% with respect to its parthenolide content by keeping at 60 degrees C and 75% relative humidity and the experiments were repeated. In another set of experiments rats were fed with 20 mg/kg Feverfew powder (equivalent to a human dose of 500 micrograms parthenolide per day) for 30 d or were i.p. injected with parthenolide (23.4 micrograms/day) for 7 d. In the same set of experiments one group of rats were fed with 15% and 77% degraded Feverfew powder in the same dose as mentioned above. After 30 days the effects of the above were observed on 5-HT and d-fenfluramine. Feverfew was specially formulated and tested for stability under accelerated conditions. RESULTS: Parthenolide (1 x 10(-5) mol/L) non-competitively antagonised the effects of d-fenfluramine but had no significant effect on 5-HT2B and 5-HT2A receptors in rat fundus and ileum at 30 min which turned significant on increasing the incubation time to 1.5 h, in rat fundus. Parthenolide (5 x 10(-5) mol/L) followed the same trend. However, Feverfew extract (1 x 10(-5) mol/L) potently and directly blocked 5-HT2B and 5-HT2A receptors and neuronally released 5-HT. At 5 x 10(-5) mol/L the extract potently and irreversibly blocked the above. Both parthenolide and Feverfew extract showed a time-dependency in their action. The extract when degraded thermally upto 10% could significantly block the 5-HT receptors and neuronal release of 5-HT, however, on further degradation it lost its inhibitory capacity markedly. Similar results were observed in rats fed orally with undergraded and degraded Feverfew powder and injected i.p. with parthenolide. Feverfew powder was more effective than any of its extracts or pure parthenolide. CONCLUSION: Feverfew powder is more potent than any of its extract or parthenolide alone in its antiserotonergic activity. Degraded Feverfew extracts show a marked decrease in their antiserotonergic activity. With thermally degraded Feverfew powder containing less contents of parthenolide no built-up antiserotonergic responses were observed after one month. This ascertains that Feverfew should be dispensed in a properly stabilized form wherein its parthenolide content is not degraded to less than 90% of the original content. (+info)
Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium.
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The in vitro activity of parthenolide against Leishmania amazonensis was investigated. Parthenolide is a sesquiterpene lactone purified from the hydroalcoholic extract of aerial parts of Tanacetum parthenium. This isolated compound was identified through spectral analyses by UV, infrared, (1)H and (13)C nuclear magnetic resonance imaging, DEPT (distortionless enhancement by polarization transfer), COSY (correlated spectroscopy), HMQC (heteronuclear multiple-quantum coherence), and electron spray ionization-mass spectrometry. Parthenolide showed significant activity against the promastigote form of L. amazonensis, with 50% inhibition of cell growth at a concentration of 0.37 microg/ml. For the intracellular amastigote form, parthenolide reduced by 50% the survival index of parasites in macrophages when it was used at 0.81 microg/ml. The purified compound showed no cytotoxic effects against J774G8 macrophages in culture and did not cause lysis in sheep blood when it was used at higher concentrations that inhibited promastigote forms. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis with gelatin as the substrate showed that the enzymatic activity of the enzyme cysteine protease increased following treatment of the promastigotes with the isolated compound. This finding was correlated with marked morphological changes induced by parthenolide, such as the appearance of structures similar to large lysosomes and intense exocytic activity in the region of the flagellar pocket, as seen by electron microscopy. These results provide new perspectives on the development of novel drugs with leishmanicidal activities obtained from natural products. (+info)
Migraine and tension headache--a complementary and alternative medicine approach.
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BACKGROUND: Migraine and tension headache are common--affecting up to 10% and 40% of the Australian population respectively--and result in significant reduction in social activities and work capacity for sufferers. OBJECTIVE: This article considers the evidence for the use of a range of complementary therapies and treatment in the prevention and management of both migraine and tension headache. DISCUSSION: Migraine and tension headache can have many precipitating factors. Considering dietary and environmental factors complements a migraine/headache consultation. There is evidence for the role of mind-body approaches, nutritional supplements such as riboflavin and magnesium, and acupuncture in the treatment of headache. By using a holistic approach we may be able to tailor a treatment program that is both effective and safe. (+info)
Parthenium dermatitis treated with azathioprine weekly pulse doses.
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BACKGROUND: Parthenium dermatitis is a serious problem in India. Corticosteroids are the mainstay of treatment but the prolonged use of corticosteroids can cause serious side effects. Azathioprine used in daily doses has been shown to be effective. AIM: We have evaluated the effectiveness of azathioprine weekly pulse doses for the treatment of parthenium dermatitis. METHODS: Twelve patients, ten males and two females, aged between 39 and 65 years (mean +/- SD = 53.5 +/- 8.7) having air-borne contact dermatitis to Parthenium hysterophorus for 3-19 years (mean = 6.33) were included in the study. The diagnosis in each patient was confirmed by patch-testing. The severity of the disease was determined by clinical severity score (CSS) on the basis of erythema, itching, type of lesions, and areas of body involved. RESULTS: The pretreatment CSS in these patients varied from 29.7 to 55.5 (mean +/- SD: 40.40 +/- 7.95). After clinical and laboratory evaluation, the patients were treated with 300-mg azathioprine once-weekly doses for 6 months. Clinical and laboratory evaluations were repeated at weeks 1, 2, and then every 4 weeks until the end of therapy to evaluate the therapeutic response and side effects. The response was excellent (80-100% clearance of disease) in seven (58.33%) patients and good (60% clearance) in five (41.66%) patients. The post-treatment CSS decreased from the mean +/- SD of 40.4 +/- 7.95 to 10.9 +/- 8.43 (P = 0.002). There were no significant side effects of the therapy. CONCLUSIONS: In this preliminary open study, azathioprine in weekly pulse doses has been found to be effective without any serious adverse effects in the treatment of parthenium dermatitis. The cost of therapy with this regimen is reduced by 60%. (+info)
Analyzing factors that influence the folk use and phytonomy of 18 medicinal plants in Navarra.
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BACKGROUND: This article analyzes whether the distribution or area of use of 18 medicinal plants is influenced by ecological and cultural factors which might account for their traditional use and/or phytonymy in Navarra. This discussion may be helpful for comparative studies, touching as it does on other ethnopharmacological issues: a) which cultural and ecological factors affect the selection of medicinal plants; b) substitutions of medicinal plants in popular medicine; c) the relation between local nomenclature and uses. To analyze these questions, this paper presents an example of a species used for digestive disorders (tea and camomile: Jasonia glutinosa, J. tuberosa, Sideritis hyssopifolia, Bidens aurea, Chamaemelum nobile, Santolina chamaecyparissus...), high blood pressure (Rhamnus alaternus, Olea europaea...) or skin diseases (Hylotelephium maximum, H. telephium, Anagallis arvensis, A. foemina). METHODS: Fieldwork began on January 2004 and continued until December 2006. During that time we interviewed 505 informants in 218 locations in Navarra. Information was collected using semi-structured ethnobotanical interviews, and we subsequently made maps using Arc-View 8.0 program to determine the area of use of each taxon. Each map was then compared with the bioclimatic and linguistic map of Navarra, using the soil and ethnographic data for the region, and with other ethnobotanical and ethnopharmacological studies carried out in Europe. RESULTS: The results clearly show that ecological and cultural factors influence the selection of medicinal plants in this region. Climate and substrate are the most important ecological factors that influence the distribution and abundance of plants, which are the biological factors that affect medicinal plant selection. CONCLUSION: The study of edaphological and climatological factors, on the one hand, and culture, on the other, can help us to understand why a plant is replaced by another one for the same purposes, either in the same or in a different area. In many cases, the cultural factor means that the use of a species is more widespread than its ecological distribution. This may also explain the presence of synonyms and polysemies which are useful for discussing ethnopharmacological data. (+info)
The solution and solid state stability and excipient compatibility of parthenolide in feverfew.
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