Parthenolide Biological Activity
The active principle of feverfew (Chrysanthemum parthenium), widely used as a herbal remedy for arthritis and migraine and as a febrifuge. Antisecretory, anti-inflammatory and spasmolytic; inhibits the release of 5-HT from blood platelets (anti-secretory platelet activity. Also inhibits generation of leukotriene B4 and thromboxane B2.
Components in Fever Few or pathenolide contain anti-secretory a-methylene butyrolactone.
Inhibition of NF-kappaB activity, constitutive in many types of cancers, via either interaction with IKK or more directly with the p65 subunit of NF-kappaB, is considered one of the main mechanisms of its action
STAT and MAP kinase activities and the induction of sustained JNK activity as well as p53 activity via influencing MDM2 and HDAC1 levels lead to an increased susceptibility of cancer cells to chemo- and radiotherapy
Inflammatory Markers of Cardiovascular Disease
Systemic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, and white cell count have previously been shown to be associated with increased risk of cardiovascular events in apparently healthy populations and patients with established vascular disease (e.g., ,), and in predicting the risk of, and outcome before and after, M.I., stroke and/or peripheral vascular events in the limbs or lungs, such as PE.
C-reactive protein (hsCRP)
PAI-1 and PAI-1
There are two components to inflammation the platelet activity aspect controlled by the chemical 5-HT and adenosine.
The other is the secretory and aging component that is controlled interleukins 1 & 6 (IL1 & IL6) prostoglandin production and leukotriene B4 and thromboxane B2 .
These components eventually influence hsCRP
The last component or anti-apoptoic influence is discussed
Heptinstall et al (1986) Compounds extracted from feverfew that have anti-secretory activity contain an α-methylene butyrolactone unit. J.Pharm.Pharmacol. 38 709. PMID: 2877077.
Murphy et al (1988) Randomized double-blind placebo controlled trial of feverfew in migraine prevention. Lancet 2 189. PMID: 2899663.
Groenewegen and Heptinstall (1990) 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. 42 553. PMID: 1981582.
Sumner et al (1992) Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. Biochem.Pharmacol. 43 2313. PMID: 1319159.
Department of Medicine, University Hospital, Queen's Medical Centre, Nottingham, UK.
Three physicochemical methods (HPLC, NMR spectroscopy, and HPLC of a derivative) have been used to measure parthenolide in authenticated Tanacetum parthenium (feverfew) and in several commercial purported feverfew products. A bioassay based on inhibition of the secretory activity of blood platelets by extracts of feverfew in comparison with parthenolide was also used. Similar results were obtained for all three physicochemical assays and also for the bioassay. Thus different methodologies yield consistent values for parthenolide content of feverfew preparations. Parthenolide appears to be mainly responsible for the antisecretory effects of extracts of feverfew. Authenticated Tanacetum parthenium grown in the UK contained a high level of parthenolide in leaves, flowering tops and seeds but a low level in stalks and roots. The level of parthenolide in powdered leaf material fell during storage. The purported feverfew products varied widely in their parthenolide content and in some products parthenolide was not detected. Possible reasons for the variation in parthenolide content are discussed. Since therapeutic efficacy has only been demonstrated for preparations of feverfew that contain parthenolide, it is suggested that manufacturers of feverfew products should use measurements of parthenolide as a means of standardization and quality control.
J Pharm Pharmacol. 1990 Aug;42(8):553-7.
Department of Medicine, University Hospital, Nottingham, UK.
Extracts of the herb feverfew inhibit human blood platelet aggregation and secretion induced by a number of agents in-vitro and this may relate to the beneficial effects of feverfew in migraine. We previously identified several compounds with antisecretory activity in human blood platelets using adrenaline as the stimulant. In the present study, we have compared the inhibitory activity of one of these compounds, parthenolide, with that of crude feverfew extract. The effects of both on [14C]5-HT secretion from platelets and on platelet aggregation induced by a number of different stimulants were determined. The activating agents studied included the phorbol ester PMA, ADP, arachidonic acid, collagen, the thromboxane mimetic U46619, the calcium ionophore A23187, the diacylglycerol analogue OAG and adrenaline. The results show that there are marked similarities between the effects of feverfew extract and of parthenolide on both [14C]5-HT secretion and platelet aggregation, which is consistent with the effects of feverfew extract on platelets being brought about by parthenolide or similar compounds in the extract. Only in one case, when A23187 was used as the stimulatory agent, was there any discrepancy, which may have been due to materials in the extract other than parthenolide. Both feverfew extract and parthenolide were more effective as inhibitors of the [14C]5-HT secretion and aggregation induced by some agents and not others, and were most effective as inhibitors of the [14C]5-HT secretion (but not the aggregation) induced by PMA. This suggests that the effects of feverfew/parthenolide on the protein kinase C pathway warrants further study.
Compounds extracted from feverfew that have anti-secretory activity contain an alpha-methylene butyrolactone unit.
COMPOUNDS EXTRACTED FROM FEVERFEW THAT HAVE ANTI-SECRETORY ACTIVITY CONTAIN AN ALPHA-METHYLENE BUTYROLACTONE UNIT.
Extracts of feverfew inhibit secretion of granular contents from platelets and neutrophils and this may be relevant to the therapeutic value of feverfew in migraine and other conditions. In this investigation we fractionated an extract of feverfew and obtained eleven fractions with antisecretory activity. The activity. The active fractions, together with two fractions that were devoid of anti-secretory activity, were examined using 1H NMR and infrared spectroscopy. All the active fractions (but neither of the inactive fractions) contained compounds with an alpha-methylene butyrolactone unit. Five compounds that contain this unit were identified as parthenolide, 3-beta-hydroxyparthenolide, secotanapartholide A, canin and artecanin, all of which are sesquiterpene lactones. It is very likely that these and other sesquiterpene lactones that contain an alpha-methylene butyrolactone unit are responsible for the anti-secretory activity in extracts of feverfew.
J Pharm Pharmacol. 1990 Aug;42(8):553-7.
Pharmacology Group, King's College London, U.K.
Leaves or infusions of feverfew, Tanacetum parthenium, have long been used as a folk remedy for fever, arthritis and migraine, and derived products are widely available in U.K. health food shops. Previous reports have suggested interactions with arachidonate metabolism. Crude chloroform extracts of fresh feverfew leaves (rich in sesquiterpene lactones) and of commercially available powdered leaves (lactone-free) produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel. Isolated lactones (parthenolide, epoxyartemorin) treated with cysteine (to neutralize reactive alpha-methylene butyrolactone functions of the sesquiterpenes). Inhibition of eicosanoid generation appeared to be irreversible but not time-dependent. We conclude that feverfew contains a complex mixture of sesquiterpene lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis of high potency, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb
Postepy Hig Med Dosw (Online). 2010 Mar 16;64:100-14.
Zakład Biologii Molekularnej Nowotworów, Wydział Lekarski Uniwersytetu Medycznego w Łodzi.
Parthenolide, a sesquiterpene lactone derived from the leaves of feverfew (Tanacetum parthenium), is considered a main bioactive component of this herb. Feverfew has been used orally or as an infusion for the treatment of migraine, arthritis, fever, and stomachache. Besides its anti-inflammatory and anti-migraine properties, parthenolide also shows anticancer activities in a variety of cell lines. It contains an alpha-methylene-gamma-lactone ring and an epoxide moiety which are able to interact with nucleophilic sites of biologically important molecules. Parthenolide modulates multiple targets, thereby contributing to its various in vitro and in vivo effects. Inhibition of NF-kappaB activity, constitutive in many types of cancers, via either interaction with IKK or more directly with the p65 subunit of NF-kappaB, is considered one of the main mechanisms of its action. In addition, inhibition of STAT and MAP kinase activities and the induction of sustained JNK activity as well as p53 activity via influencing MDM2 and HDAC1 levels lead to an increased susceptibility of cancer cells to chemo- and radiotherapy. At the epigenetic level, parthenolide reduces HDAC1 level and, by inhibiting DNMT2 activity, induces global hypomethylation of DNA, which can restore the expressions of some suppressor genes. Moreover, this compound reduces the cellular level of GSH in cancer cells, followed by ROS accumulation and apoptosis. A unique property of parthenolide is its ability to induce cell death mainly in cancer cells, while sparing healthy ones and it also protects normal cells from UVB and oxidative stress. More remarkably, it seems to have the potential to target some cancer stem cells. Its wide array of biological activity and low toxicity make parthenolide a very promising drug with multi-pharmacological potential, largely dependent on the cellular context.
Chem Biol. 2001 Aug;8(8):759-66.
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520-8103, USA.
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.
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.
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
by Rob Hawkins
There is an ever increasing body of evidence suggesting that inflammation at a cellular level is one of the main contributing factors for disease and may accelerate the aging process. The argument goes that as inflammation at a cellular level increases cells become less pliable thus becoming less efficient at conducting the daily business that sustains one's general health.
For doctors skilled in the art of naturopathy this idea is very much at the core of their approach to wellness; though in a roundabout way. For example one of the primary linchpins of naturopathic medicine is liver health with the premise being that a healthy liver keeps the blood free from toxins. We now know that toxins cause internal inflammation leading to cellular denigration. This naturopathic approach used for thousands of years may soon be proven correct.
As far as the aging process goes inflammation causes skin tissue to wrinkle and age. There are many, many, topical creams and lotions specially formulated to eliminate wrinkles and give your skin that youthful glow. But from the less than stellar results of most of the people I know this claim may be falling short of expectations due to the constant damage being done internally. In other words even the best of these products are simply putting a Band-Aid on the damage rather than addressing the cause.
What can I do to reduce the impact of internal inflammation?
I wish I could tell you that there is a magic bullet that will turn back the clock overnight but I can't. What I can tell you is that there a number of steps that have produced tangible results in a relatively short period of time for myself and my family. If you have a couple of extra minutes to spare why don't we look at four of these.
*Diet modification: Adding foods to your diet that have known antioxidant and liver health properties is a good place to start. Parsley (liver), radishes, cucumbers, watercress, blueberry juice, and sweet potatoes (skin health/aging) all seem to poses certain properties which may reduce inflammation and improve skin health.
*Colon cleansing: Some believe that the buildup of fecal matter in the intestines over time continually bombards the body with toxins. By cleansing the colon and small intestines of this garbage once in a while you will be reducing inflammation and improving vitamin and mineral absorption. A cautionary note: Colon cleansing is not for everyone and products vary widely so do your homework on this one.
*Herbal and homeopathic anti-aging/liver health supplements: There are a handful of excellent herbal and homeopathic products which attack inflammation from the inside out while improving liver and immune function. These products are generally considered to be very safe and quite affordable.
*Omega 3 fatty acids: In recent years fish oil supplements high in omega 3 fatty acids have become a staple in the world of cardiovascular health. They also seem to help reduce cellular inflammation with one study suggesting they may be useful as a supplemental treatment for over 60 different inflammation driven diseases.
In conclusion, the four steps above are only the tip of the iceberg when it comes to reducing internal inflammation. Other suggestions that might help temporarily send father time packing are avoiding tobacco smoke, staying active, saying no to trans fats, and reducing the intake of damaging homocysteines (amino acids found in protein that are neutralized by B vitamins).
Rob Hawkins is an enthusiastic advocate for the use of natural health products and natural living with over 10 years experience in the field. Learn more about natural remedies and natural health at http://purchaseremedies.com