What if we told you that there is a natural active ingredient as powerful as antidepressants with fewer side effects. That this active ingredient acts on our brain by modulating certain neurotransmitters such as serotonin in order to provide a powerful anti-stress effect. Well know that this active principle exists, it is called “parthenolide” .
Parthenolide is a natural active ingredient found in several plants including chamomile . It has been known to scientists and studied for several decades in the treatment of many diseases . Indeed, parthenolide is a molecule capable of interacting with many receptors in the human body. This ability has made him a preferential candidate for developing new treatments for cancer , migraine , obesity, cardiovascular disorders and even anxiety and depression.
The beneficial effects of parthenolide have been demonstrated several times in in vitro clinical studies, in animals and in humans. Just type his name in some scientific database to find a multitude of publications about him.
The benefits of parthenolide:
Parthenolide has many benefits . It is a powerful antioxidant and therefore opposes free radicals which destroy our cells. It is also a robust anti-inflammatory and neuromodulator . This ability to modulate certain neuroreceptors allows it to have a direct action on our brain . It will modulate its activity and soothe it. Studies that record the electrical activity of the brain have shown the relaxing effect of parthenolide administration.
Benefits from 0.05mg per day
You don't have to take extravagant amounts of parthenolide to feel the benefits. Indeed, from 0.05 mg per day , parthenolide plays its protective and soothing role.
Its association with salicin potentiates its effect
Recent studies have shown that its association with salicin , which is a natural anti-inflammatory, can potentiate the action of parthenolide . The synergistic action of these two molecules is proven, but still misunderstood. To treat migraine or chronic pain, the combination of the two compounds multiplies the results by three. In depression, stress or anxiety , this combination can significantly improve the quality of life of patients.
How to use and take parthenolide
Unfortunately, it is not enough to take chamomile infusion to get a dose of parthenolide. Indeed, naturally chamomile contains parthenolide, but in extremely small quantities. It is necessary to have plant extracts which have been naturally enriched with parthenolide and which are titrated , that is to say that a dosage has been carried out to guarantee a minimum content of the active ingredient .
When this is the case, the statement is written on the packaging and clearly specifies the parthenolide content. Oral administration is recommended, preferably in capsules . An infusion, for example, will scald the active ingredient and the plant will lose all its effectiveness. Extracts at 0.1% parthenolide help ensure a sufficient amount and it is preferable that salicin be added for maximum effectiveness.
Herba Mig a combination parthenolide and salicin for stress and anxietyOur laboratory has studied parthenolide and salicin for many years. In partnership with INSERM, we analyzed the effects of these active ingredients on serotonin receptors, as well as on pain mediators. Our research led to the formulation of Herba Mig which combines parthenolide (90mg at 0.1%) , salicin , but also vitamins B2 and B12 as well as an essential coenzyme , Q10 . This complex has given excellent results in clinical studies on stress , depression and even migraine .
To learn more about parthenolide:
Tanacetum parthenium contains guaianolides, eudesmanolides and germacranolides in significant amounts. Parthenolide is germacranolide considered to be the main active ingredient in the plant (Figure 10).
It was first isolated in 1965 (Atta-ur-Rahman 2018). It is a terpene with 15 carbon atoms, 3 isoprenes and an α-methylene-γ-lactone ester ring: 4.5 epoxygermacra-(10),11(13)-dien-12,6-lactone.
Parthenolide is absorbed from the intestinal mucosa via a passive diffusion system. It then interacts with the thiol functions of certain protein residue cysteines. Through this reaction, parthenolide would be able to influence the biological activity of the protein. It establishes a conjugated covalent bond between its α-β-unsaturated carbonyl function and the sulfhydril residues of the nucleophile, resulting in alkylation through the Michael addition reaction (Freund et al. 2020).
Parthenolide can therefore undergo alkylation reactions with intracellular nucleophiles, such as cysteines, glutathione and numerous cellular proteins which possess a thiol group, to form an adduct responsible for the pharmacological properties observed.
The majority of pharmacological effects caused by sesquiterpene lactones are explained by their ability to react with enzymes and transcription factors modifying essential functions of the cell (Freund et al. 2020). Parthenolide derivatives like 11, 13 dihydroparthenoids show no biological activity (Atta-ur-Rahman 2018).
The main difference between these two molecules is the saturation of the exocycle in 11-13, suggesting the biological importance of the unsaturated α, β carbonyl compound. Parthenolide also has an epoxide function (electrophile) capable of reacting with alkylating agents (nucleophile). This makes it possible to increase its biological activity compared to other sesquiterpene lactones which do not have it.
However, Neukirch and co-workers report that the spatial arrangement of the sesquiterpene skeleton is more important than its functional groups in its pharmacological efficacy (Neukirch et al. 2003).
2. Role of parthenolide in the anti-inflammatory action of Tanacetum parthenium:
The anti-inflammatory activity of Tanacetum parthenium is mostly attributed to parthenolide. Already in 1989, an English study had shown the effectiveness of the plant in the treatment of rheumatoid arthritis (Pattrick et al. 1989). This effect would be due to the pharmacological inhibition of pro-inflammatory cytokines and the synthesis of prostaglandins. Thus in vitro studies have shown the ability of parthenolide to inhibit the production of cytokines and pro-inflammatory interleukins by macrophages (Hwang et al. 1996).
This inhibitory activity is mainly due to an action on the NF-κB pathway (Hehner et al. 1999). This pathway plays an important role in immune and inflammatory responses. It is also involved in the anti-apoptotic response, both during normal differentiation and carcinogenesis phenomena (Karin et al. 2006). The mechanism of action of parthenolide on the NF-κB pathway is not completely understood.
Hehner's team however reported that the activity of parthenolide would be due to an inhibition of the degradation of the NF-κB-IκB complex (Hehner et al. 1999). Parthenolide would interact with the IKK complex, particularly by inhibiting IKKβ activity (Kwok et al. 2001). Other authors believe that it is a direct alkylation of parthenolide on the p65 subunit of the NF-κB dimer (García-Piñeres et al. 2001).
However, there could be different mechanisms depending on cell lines. The Garcia-Pineres team studied the effect of parthenolide on the NF-κB pathway in four different cancer cell lines and also came to the conclusion of a direct action by alkylation on the p65 subunit of the NF-κB complex. (García-Piñeres et al. 2004). Inhibition of prostaglandin synthesis is another key activity of Tanacetum parthenium's anti-inflammatory properties. They are synthesized from arachidonic acid by the action of cyclooxygenases. Studies on parthenolide show that it inhibits prostaglandin synthesis (Takai et al. 2013; Pugh et al. 1988; Collier et al. 1980). Associated with this inhibition, a decrease in the expression of cyclooxygenase 2 mRNA is found (Rummel et al. 2011).
However, parthenolide does not appear to specifically target COXs, as for example salicin does. It would therefore seem that the anti-inflammatory action of parthenolide differs from that of salicylates, since no inhibition of cyclo-oxygenation is observed (Collier et al. 1980). While sesquiterpene lactones have mainly been studied to explain the anti-inflammatory activity of Tanacetum parthenium, they are not the only ones responsible for its effects. Researchers interested in the flavonoids of the plant have shown an inhibitory activity of cyclo-oxygenases and 5-lipoxygenases by the latter, more particularly due to 6-hydroxyflavonol (Williams et al. 1999; Long et al. 2003).
3. Tanacetum parthenium in the treatment of migraine
Tanacetum parthenium has long been used to treat migraines, but clinical trials report mixed results. In 2004, a review of the literature based on five clinical trials for a total of 343 patients failed to conclude that the plant was effective in preventing seizures (Pittler et al. 2004).
In 2015, the same authors published an update of this analysis, including new trials with stricter methodology (Wider et al. 2015). It is mainly the MIG99 study, randomised, multicentre, double-blind and using a hypercritical CO 2 extract of Tanacetum parthenium, which made it possible to counterbalance this analysis (Diener et al. 2005). The data then covers 561 migraine patients in total. A reduction in attack frequency of 1.9 attacks was reported in patients using the plant compared to 1.3 in the placebo group, a significant difference of 0.6. However, no difference was observed in the duration and intensity of the crisis.
The variable results of studies evaluating the effectiveness of Tanacetum parthenium in the prevention of migraine are mainly due to a methodological problem. Either the duration of the study is too short, because the benefits of the plant are only felt after several months; or the inclusion criteria are not correctly defined. The extract of the plants used also plays a role in the variability of the results obtained.
Few studies measure the quantity of active ingredients and particularly parthenolide contained in their extract. However, depending on the extract (whole plant, leaves or flowers), the percentage of parthenolide varies greatly (0 to 5%) (Heptinstall et al. 1992). The effectiveness observed in the MIG99 study may be due to this particularity of extraction, which gives the ingredient a higher level of active ingredient than those used in other clinical trials (Diener et al. 2005).
In addition to its anti-inflammatory effects, several other mechanisms could explain the effectiveness of the plant in preventing migraines:
has. Action on smooth muscles:
Sesquiterpene lactones appear to have antispasmodic activity in smooth muscles through an α-blocking effect. They are capable of inhibiting, in a mouse model, contractions of the aorta induced by serotonin and phenylephrine (α1-adrenergic agonist) (Orona-Ortiz et al. 2018). Tanacetum parthenium leaf extracts have been shown to inhibit aortic contraction and dilation in rabbits (Barsby et al. 1992). This inhibition was concentration dependent, non-competitive and irreversible. The effect is observed with or without the presence of the endothelium.
The same team showed, by electrophysiological recordings, that the extract of Tanacetum parthenium was also capable of inhibiting the contraction of vascular smooth muscles induced by a potassium current (Barsby et al. 1993).
The researchers also showed that parthenolide could non-competitively inhibit the spasmogenic response caused by serotonergic drugs, such as fenfluramide or dextroamphetamine in the stomach. The mechanism of action associated with parthenolide would not directly involve the inhibition of 5-HT2 receptors, but would be localized at the level of serotonin stored in the vesicles of neurons (Béjar 1996). Thus, the antiserotoninergic activity of Tanacetum parthenium could enable it to oppose – in part – the vasodilation of the meningeal vessels during migraine attacks.
b. Action on platelets
Parthenolide would be able to bind to the sulfhydril groups of enzymes involved in platelet aggregation and serotonin release (Groenewegen et al. 1990; Groenewegen et al. 1986). Weber's team showed an activity preferentially targeted at 5-HT 2A receptors (Weber et al. 1997). Another team confirms the anti-serotonergic effect of parthenolide; however, it would not directly target 5HT 2A receptors, but could influence the release of serotonin at the level of its vesicular storage through indirect pathways (Mittra et al. 2000; Pareek et al. 2011).
A recent study found this anti-serotonergic action in parthenolide derivatives contained in the leaves of Stizolophus balsamita (Nawrot et al. 2019). This activity is not specific to parthenolide and has also been found for other sesquiterpene lactones (Atta-ur-Rahman 2018).
vs. Action on TRPA1 receptors
Recent studies have opened the way for an agonist activity of parthenolide on TRPA1 receptors (Materazzi et al. 2013). Indeed, in the absence of the receptor, the application of parthenolide does not result in any cellular activity. The α-methylene-γ-lactone ring as well as the epoxide would allow the formation of a covalent bond by a Michael addition reaction with the receptor. It is assumed that the reaction takes place on the cysteines of interest in the N-terminal part (C621, C641 and C665). It was subsequently demonstrated by electrophysiological recordings that parthenolide was capable of desensitizing TRPA1 (Materazzi et al. 2013; Nassini et al. 2014).
Following a first application which activates the receptor, a second application of parthenolide, or even AITC, a TRPA1 agonist, a few seconds later, does not cause any response, which suggests desensitization of the receptor. -this. Parthenolide is therefore not a pure TRPA1 agonist, but is qualified as a partial agonist (Ghantous et al. 2013).
By desensitizing the TRPA1 receptors of the nociceptive neurons of the trigemino-vascular system, parthenolide reduces the release of CGRP by the latter. Injection of parthenolide at 4 mg/kg intraperitoneally in a mouse model shows inhibition of meningeal vasodilation evoked by intranasal injection of acrolein (TRPA1 agonist) and, interestingly, by intranasal injection of capsaicin (TRPA1 agonist). of TRPV1).
Thus, without specifically targeting TRPV1, parthenolide through its action on TRPA1 would be able to modulate the response induced by TRPV1 agonists. It is also interesting to note that meningeal vasodilation caused by the administration of sodium nitroprusside, a powerful vasodilator which acts by release of NO, is not inhibited by the prior injection of parthenolide (Materazzi et al. 2013). .
According to traditional Indian and Chinese medicine, Tanacetum parthenium is often used in combination with other ingredients with anti-inflammatory properties. In India, the boswellia serrata plant and turmeric are very often associated with Tanacetum parthenium, as is the bark of Salix Alba.
In 2006, the Vitrobio laboratory, within the University Hospital of Clermont-Ferrand, with the help of neurologist Jean-Claude PECHADRE, evaluated the effectiveness of a combination of Tanacetum parthenium and Salix alba in the prophylactic treatment of migraine. (Shrivastava et al. 2006). The observational study involved 12 migraine patients who were administered 150 mg of Salix alba with 1.5% salicin, as well as the same dose of Tanacetum parthenium, with 0.2% parthenolide. After three months of treatment, 70% of patients report having a reduction in seizure frequency of at least 50%. The association was then patented (WO9839018), but never commercialized.
The Pilèje laboratory meanwhile evaluated, in 62 patients, the effectiveness of the combination of Tanacetum parthenium, with coenzyme Q10 and magnesium, at a dose of 100 mg for the three ingredients, in the prevention of migraine attacks. . After three months of treatment, 75% of patients reported having a decrease in seizure frequency of at least 50% (Guilbot et al. 2017).
The studies of these two laboratories are observational and do not include a placebo group. The results obtained are however encouraging to hope to develop new treatments based on Tanacetum parthenium in the prevention of migraine attacks.
It is from these results that Di Giacomo's team recently became interested in the association of Salix alba with Tanacetum parthenium in a mouse model of DCE (Di Giacomo et al. 2019). The results indicate that the combination of plants opposes the effects induced by DCE. Markers of oxidative stress and inflammation such as lactate dehydrogenase (LDH) and certain nitrites are significantly reduced in the presence of the extracts. Similarly, the 5HIAA/serotonin ratio is markedly reduced. It is interesting to note that these effects are increased when the plants are associated.
Secondly, this same team looked at astrocytic cells exposed to hydrogen peroxide. They note a preventive effect of plant extracts against the cytotoxicity of hydrogen peroxide and a reduction in cell apoptosis. Again, the combination of the two extracts shows better results.