Petasin

Abstract: Background Priming of eosinophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) and subsequent stimulation with platelet-activating factor (PAF) or the anaphylatoxin C5a is associated with a rapid production of leukotrienes (LTs) and release of eosinophil cationic protein (ECP). Objective This study was designed to determine the effects of the sesquiterpene esters petasin, isopetasin and neopetasin on LT generation and ECP release in eosinophils in vitro. Methods The model of eosinophil activation described above was used to induce LT production and ECP release. Cells were incubated with petasins and control inhibitors prior to priming and stimulation. To analyse intracellular steps of eosinophil activation and determine potential drug targets, some key signalling events were studied. Activity of cytosolic phospholipase A 2 (cPLA 2 ) was measured by analysing the generation of arachidonic acid (AA). Translocation of 5-lipoxygenase (5-LO) was observed using immunofluorescence microscopy. Intracellular calcium concentrations [Ca 2+ ] i were measured by a bulk spectrofluorometric assay. Results Whereas all three compounds inhibited LT synthesis, ECP release from eosinophils was blocked by petasin only, but not isopetasin or neopetasin. Similarly, PAF- or C5a-induced increases in [Ca 2+ ] i were completely abrogated by petasin only, whereas isopetasin and neopetasin had significant lower blocking efficacy. Moreover, only petasin, but not isopetasin or neopetasin, prevented increases in cPLA 2 activity and 5-LO translocation from the cytosolic compartment to the nucleus envelope in calcium ionophore-stimulated eosinophils. Conclusion These data suggest that different petasins may at least partially block different intracellular signalling molecules. To reduce LT synthesis, isopetasin and neopetasin may act at the level of or distal to 5-LO. In contrast, petasin may inhibit inflammatory effector functions in human eosinophils by disrupting signalling events at the level of or proximal to phospholipase Cp (PLCp), besides its potential inhibitory activity within mitogen-activated protein kinase (MAPK) and LT pathways.

Abstract: In vivo and in vitro studies were carried out to examine the putative hypotensive actions of S-petasin, a sesquiterpene extracted from the medicinal plant Petasites formosanus. Intravenous S-petasin (0.1-1.5 mg/kg) in anesthetized rats produced a dose-dependent hypotensive effect. In isolated aortic ring, isometric contraction elicited by KCl or the L-type Ca2+ channel agonist Bay K 8644 was reduced by S-petasin (0.1-100 microM), an action not affected by the cyclooxygenase inhibitor indomethacin, nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine, guanylyl cyclase inhibitor methylene blue, or removal of vascular endothelium. Pretreatment with S-petasin for 10 min shifted the concentration-response curve for KCl (15-90 mM)-induced contraction to the right and reduced the maximal response. In Ca2+-depleted and high K+-depolarized aortic rings preincubation with S-petasin attenuated the Ca2+-induced contraction in a concentration-dependent manner, suggesting that S-petasin reduced Ca2+ influx into vascular smooth muscle cells (VSMCs). Moreover, in cultured VSMCs, whole-cell patch-clamp recording indicated that S-petasin (1-50 microM) inhibited the L-type voltage-dependent Ca2+ channel (VDCC) activities. Intracellular Ca2+ concentration ([Ca2+[(i)) estimation using the fluorescent probe 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'-methylphenoxy)-ethane-N,N,N,N-tetraacetic acid pentaacetoxymethyl ester indicated that S-petasin (10, 100 microM) suppressed the KCl-stimulated increase in ([Ca2+[(i)). Taken together, the results suggested that a direct Ca2+ antagonism of L-type VDCC in vascular smooth muscle may account, at least in part, for the hypotensive action of S-petasin.

Abstract: Background Butterbur ( Petasites hybridus ) contains the active ingredient petasin, which exhibits antileukotriene and antihistamine activity. Previous studies of intermittent allergic rhinitis (IAR) have demonstrated a comparable response to butterbur compared with a histamine H 1 -receptor antagonist on the 36-Item Short-Form Health Survey quality-of-life score. However, there has been no placebo-controlled study of the effects of butterbur use on objective and subjective outcomes in IAR. Objective To evaluate the effects of treatment with butterbur vs placebo on objective and subjective outcomes in IAR. Methods A doubleblind, placebocontrolled, crossover study was carried out during the grass pollen season in Tayside, Scotland. Thirty-five patients (14 men and 21 women) with IAR received butterbur, 50 mg twice daily, or placebo for 2 weeks. Domiciliary measurements were taken in the morning and evening for peak nasal inspiratory flow (PNIF) (the primary outcome variable), nasal and eye symptoms, and rhinoconjunctivitis-specific quality-of-life score. Results Butterbur treatment had no significant effect on PNIF, total nasal symptom score, eye symptom score, or quality of life compared with placebo use. Mean (SEM) morning and evening PNIF values were 107 (6) and 114 (6) L/min, respectively, for butterbur vs 105 (6) and 117 (6) L/min for placebo. Mean (SEM) morning and evening total nasal symptom scores (maximum total score, 12) were 3.4 (0.4) and 3.5 (0.4), respectively, for butterbur vs 3.7 (0.3) and 3.8 (0.4) for placebo. Conclusions There was no significant clinical efficacy of butterbur use vs placebo use on objective and subjective outcomes in IAR. Further studies are now indicated to investigate the use of butterbur in persistent allergic rhinitis.

Abstract: Reactive oxygen radicals have been implicated in the pathophysiology of many neurologic disorders and brain dysfunctions. Kainic acid has been used as a model agent for the study of neurotoxicity of various excitatory amino acids, since it induces neuronal damage through excessive production of reactive oxygen species. Petasites japonicus MAX (butterbur), cultivated as culinary vegetables in Eastern Asia, contains various kinds of phenolic compounds as well as sesquiterpenes, such as petasin. In European countries, the extracts from roots of Petasites species have been used in the therapy of headache or asthma. The objective of our study is to examine the neuroprotective action of the Petasites japonicus MAX (butterbur) extract against oxidative damage in the brain of mice treated with kainic acid. Male ICR mice, 6–8 weeks of age, were administered orally the butanol fraction from methanol extract of Petasites japonicus (BMP) or its subfraction (BMP–I or BMP–II) for 5 consecutive days. Thirty min after the final administration, the animals were challenged s. c. with kainic acid (45 mg/kg), and neurobehavioral activities were monitored. In addition, biomarkers of oxidative stress and neuronal loss in the hippocampus for the biochemical, neurobehavioral,morphological evaluations were analyzed 2 days after the kainic acid challenge. During 5–day treatment with BMP or BMP–1, the body weight gain was not significantly different from that of vehicle– treated control animals. Administration of kainic acid alone induced severe epileptiform seizures, causing a lethality of approximately 50%, and injuries of pyramidal cells in the hippocampus of mice which survived the challenge. Kainic acid exposure also resulted in a remarkable decrease in total glutathione level and glutathione peroxidase activity, and an increase in the thiobarbituric acid–reactive substance (TBARS) value in brain tissues. In comparison, coadministration with BMP (400 mg/kg) reduced the 54% lethality of mice, administered with kainic acid alone, to 25 % (P <0.05). Moreover, BMP at the same dose restored the levels of reduced glutathione and TBARS to control values (P <0.05). In further studies, BMP–I (200 mg/kg) ameliorated significantly (P <0.05) the kainic acid–induced behavioral signs, such as seizure activity, and all mice administered with BMP–I (200 mg/kg) survived the kainic acid toxicity. Consistent with the above, the administration with BMP–1 remarkably attenuated the neurobehavioral signs and neuronal loss in hippocampal CA1 and CA3 regions. On the basis of these results, the butanol fraction, especially BMP–I, of Petasites japonicus MAX extract is possibly suggested to be a functional agent to prevent oxidative damage in the brain of mice.