Abstract
Migraine is a frequent and often disabling disease. Treatment is unsatisfactory in many patients. A disturbed dynamic balance between excitatory and inhibitory signal processing with enhanced cortical activity probably underlies common forms of migraine. Presynaptic voltage-gated Ca2+ channels are critical determinants of neurotransmitter release and also contribute to trigeminovascular signal transduction. Because clinical evidence exists for migraine-prophylactic actions of Petasites hybridus extracts, we investigated whether petasins comprising the main constituents of the extract inhibit currents through presynaptic Cav2.1 channels expressed in Xenopus laevis oocytes. P. hybridus extract (0.02 mg/ml), petasin, neopetasin, isopetasin, S-petasin, and iso-S-petasin (50 μM) were weak tonic blockers of Cav2.1-mediated barium currents (IBa) during infrequent depolarizations (0.1 Hz), but their inhibitory potency increased at higher stimulation rates (1 Hz), indicating preferential block of open and/or inactivated channels. Sulfur-containing compounds (S-petasin, Iso-S-petasin) were the most potent significantly promoting the accumulation of Cav2.1 channel in inactivated states during pulse trains (IBa decrease during 1-Hz pulse trains: control, 45%, S-petasin, 79%; iso-S-petasin, 80%). For the Eucalyptus williamsiania sesquiterpenes α- and γ-eudesmol, a comparable use-dependent inhibition was found in addition to a tonic block component. α-Eudesmol and petasins accelerated the voltage-dependent inactivation of Cav2.1 channels during depolarizations. We demonstrate that S-petasin, iso-S-petasin, and eudesmol are Cav2.1 channel inhibitors preferentially acting as use-dependent channel blockers and with the sulfur-containing substituent in position 3 of the petasins serving as important functional feature. The Cav2.1-inhibitory properties of these petasins may contribute to migraine-prophylactic properties described for P. hybridus extracts.
Footnotes
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This work was supported by the Austrian Science Fund [Grant FWF P17159]; and the University of Innsbruck and the Tiroler Wissenschaftsfonds [UNI-0404/353].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.151183.
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ABBREVIATIONS: VGCC, voltage-gated Ca2+ channel; LTCC, L-type (Cav1) Ca2+ channel; HPLC, high-performance liquid chromatography; IBa, inward Ba2+ current; DMSO, dimethyl sulfoxide; τfast, τslow, time constants of fast and slowly inactivating current components; MS-222, tricaine (ethyl 3-aminobenzoate) methanesulfonate.
- Received January 20, 2009.
- Accepted April 14, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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