The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects

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 n M and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes ( α 1−3,5,6 β 2 γ 2 S) indicating positive allosteric properties. Maximal stimulation at α 1 β 2 γ 2 S was observed with 10 μ M hispidulin. In contrast to diazepam, hispidulin modulated the α 6 β 2 γ 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 μ M , the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.British Journal of Pharmacology (2004) 142 , 811–820. doi: 10.1038/sj.bjp.0705828