Application in migraine treatment
Butterbur (Petasites hybridus) has been used for centuries in Northern Eurasia and America for fever, respiratory disease, and spasm treatment. Its extract was recently observed for migraine prevention due primarily to petasin and isopetasin, the active constituents. However, petasin is unstable and spontaneously converts to isopetasin, and thus standardization is unavoidable.
Several hypotheses have been put forward to elucidate the anti-migraine effects of petasin and isopetasin. These compounds inhibit enzymes such as phospholipase A2, lipoxygenase, and cyclooxygenase-2 (COX-2), leading to a reduction in inflammatory mediators like leukotrienes [4] and prostaglandins, particularly PGE2, which are implicated in migraine inflammation. Additionally, petasins influence L-type high-voltage calcium channels, [5] which play a role in pain modulation. They also exhibit antimuscarinic activity [6] and inhibit the release of calcitonin gene-related peptide (CGRP), a part in the onset of migraine attacks. [7] [8]
In vivo tests on mice, rats, and human native and recombinant systems revealed that isopetasin activates TRPA1 [9] channels of sensory neurons preferentially with a contribution to desensitization of nociceptor and without activation of TRPV1 or TRPV4 channels. TRPA1 and TRPV1 ion channels, which are located in nociceptive sensory neurons, are involved in pain sensation and are important because they allow the passage of Ca²⁺ ions. They are drug targets. Mustard oil activation of TRPA1 and capsaicin activation of TRPV1 lead to the release of CGRP [10] from dura mater and trigeminal ganglion but Petasites hybridus inhibits these ion channels, reducing CGRP release in meningeal afferents during migraine attacks. [7] [8]
Like parthenolide, [11] isopetasin induces desensitization of peptidergic primary sensory neurons, either specifically targeting the TRPA1 channel or extending to other TRP channel activators and non-TRP depolarizing agents. The shift from homologous to heterologous desensitization appears to depend on the concentration and duration of isopetasin exposure.
The ability of isopetasin to inhibit neurogenic inflammation beyond the trigeminal innervation may explain its effectiveness in inflammatory conditions like arthritis [12] and allergic rhinitis. [13]
Clinical studies have demonstrated that butterbur extracts containing isopetasine can reduce migraine frequency by up to 50%, [14] [15] offering effectiveness comparable to conventional treatments like beta-blockers but with fewer side effects. However, it is essential to ensure the use of purified, PA-free extracts, as raw butterbur contains pyrrolizidine alkaloids (PAs), which can be toxic to the liver. [16]
Application in cancer treatment
Isopetasin and S-isopetasin, can address the problem of resistance to anti-cancer drugs, notably by targeting P-glycoprotein (P-gp). This protein, encoded by the ABCB1 gene, belongs to the ABC family of transporters and is found in the plasma membranes of many cells. Its role is to limit the intracellular accumulation of various drugs by expelling them, which contributes to the drug resistance observed in cancer cells.
Studies have shown that isopetasine and S-isopetasine bind to specific amino acids of the P-gp protein, thereby disrupting its function. Their mode of action is similar to that of verapamil, a first-generation P-gp inhibitor. These molecules appear to have two main effects: they increase the accumulation of anti-cancer drugs in resistant cells, and they activate the P-gp ATPase enzyme, responsible for converting ATP into ADP. As drug expulsion by P-gp requires energy from ATP, this activation disrupts the process, reducing P-gp's ability to reject these drugs. In addition, P-gp dysfunction can cause stress in the mitochondria, leading to increased ATP production and reactive oxygen species (ROS). These excess ROS can trigger cell death (apoptosis) in tumor cells. Thus, isopetasin and S-isopetasin could induce cancer cell death by oxidative stress, reinforcing their therapeutic potential. This dual action, as both P-gp inhibitors and cancer cell toxicants, makes these compounds interesting candidates for treating treatment-resistant cancers. [17]
