title: The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effects.
abstract: The functional characterization of hispidulin (4',5,7-trihydroxy-6-methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. After chemical synthesis, hispidulin was investigated at recombinant GABA(A)/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nm and higher stimulated the GABA-induced chloride currents at tested receptor subtypes (alpha(1-3,5,6)beta(2)gamma(2)S) indicating positive allosteric properties. Maximal stimulation at alpha(1)beta(2)gamma(2)S was observed with 10 microm hispidulin. In contrast to diazepam, hispidulin modulated the alpha(6)beta(2)gamma(2)S-GABA(A) receptor subtype. When fed to seizure-prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg(-1) body weight (BW) per day) and diazepam (2 mg kg(-1) BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). Permeability across the blood-brain barrier for the chemically synthesized, (14)C-labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (K(in)) of 1.14 ml min(-1) g(-1), measurements approached the values obtained with highly penetrating compounds such as diazepam. Experiments with Caco-2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 microm, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.
authors.affiliation: Food Chemistry, University of Würzburg, Würzburg D-97074, Germany. kavva@pzlc.uni-wuerzburg.de
authors.forename: Dominique
authors.initials: D
authors.lastname: Kavvadias
authors.forename: Philipp
authors.initials: P
authors.lastname: Sand
authors.forename: Kuresh A
authors.initials: KA
authors.lastname: Youdim
authors.forename: M Zeeshan
authors.initials: MZ
authors.lastname: Qaiser
authors.forename: Catherine
authors.initials: C
authors.lastname: Rice-Evans
authors.forename: Roland
authors.initials: R
authors.lastname: Baur
authors.forename: Erwin
authors.initials: E
authors.lastname: Sigel
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Rausch
authors.forename: Peter
authors.initials: P
authors.lastname: Riederer
authors.forename: Peter
authors.initials: P
authors.lastname: Schreier
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D047310:Apigenin / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004594:Electrophysiology; D047309:Flavones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018757:GABA Modulators / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005849:Gerbillinae; D006801:Humans; D007202:Indicators and Reagents; D007553:Isotope Labeling; D007700:Kinetics; D008024:Ligands; D008297:Male; D009865:Oocytes / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000235:genetics / Q000517:prevention & control; D014982:Xenopus laevis
chemical_list: D000927:Anticonvulsants; D047309:Flavones; D018757:GABA Modulators; D007202:Indicators and Reagents; D008024:Ligands; D011963:Receptors, GABA-A; D047310:Apigenin; C055957:hispidulin