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

Abstract

Dedicated to Prof. Dr S. Ebel on his 70th birthday1 The functional characterization of hispidulin (4 0 ,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. 2 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 GABAinduced chloride currents at tested receptor subtypes (a 1À3,5,6 b 2 g 2 S) indicating positive allosteric properties. Maximal stimulation at a 1 b 2 g 2 S was observed with 10 mM hispidulin. In contrast to diazepam, hispidulin modulated the a 6 b 2 g 2 S-GABA A receptor subtype.3 When fed to seizure-prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg À1 body weight (BW) per day) and diazepam (2 mg kg À1 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). 4 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 À1 g À1 , measurements approached the values obtained with highly penetrating compounds such as diazepam. 5 Experiments with Caco-2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 mM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.

Flavonoid Actions on Receptors for the Inhibitory Neurotransmitter GABA

“…The inhibition of the GABA response at α1β2γ2S GABA A receptors expressed in oocytes in the presence of lumazenil (0.1-1 mM) was the irst deinitive report of the lumazenil-insensitive actions of lavonoids on recombinant GABA A receptors [10]. Similar lumazenil-insensitive negative modulatory actions of apigenin on recombinant GABA A receptors were subsequently reported by other investigators [11,23].…”

“…Structurally, hispidulin difers from apigenin only by the addition of a 6-methoxy substituent. In functional studies on recombinant α1β2γ2 GABA A receptors expressed in Xenopus oocytes, hispidulin was inactive when applied alone, and at concentrations up to 10 μM was found to positively modulate the efect of 4 μM GABA [23]. This positive modulation was partially blocked by lumazenil.…”

“…Using 14 C-hispidulin, the lavone was found to pass the blood-brain barrier using a rat perfusion model [23]. Further, hispidulin exhibited a lumazenil-sensitive anticonvulsant action, similar to diazepam, in seizure-prone Mongolian gerbils used as an animal model of epilepsy [23].…”

HPLC-based activity profiling for GABAA receptor modulators from the traditional Chinese herbal drug Kushen (Sophora flavescens root)

“…Evidence for in vivo activity mediated through GABA A receptor modulation has been reported for selected flavonoids. Simple flavones and flavonols such as chrysin, apigenin, wogonin, 6-methylapigenin, hispidulin, and luteolin-7-O-(2-rhamnosylglucoside) appear to induce predominantly anxiolytic effects and seem less efficient as sedatives, anticonvulsants, and myorelaxants [34,[39][40][41][42].…”

A new synthesis of novel alkenylated flavones by palladium-catalyzed cross-coupling reactions

“…They play important roles in the plant reproduction and defense and also possess a wide range of biological and pharmaceutical activities. anticonvulsive, 4 α-glucosidase inhibitor, 5 aldehyde dehydrogenase ALDH-2 inhibitor, 6 EGFR tyrosine kinase 7 and COX-2 inhibiting activity. 8 The group of 2-and 3-styrylchromones is a smaller family of chromonoids 9,10 but few representatives are known in the nature and their biological activities were also reported and reviewed.…”