Although many flavonoids have been reported to exert their neuroactivities through the benzodiazepine (BZ) site of GABA_A receptors, the underlying mechanisms for the behavioral effects of flavonoids are less understood. _A...[ Read more ]

Although many flavonoids have been reported to exert their neuroactivities through the benzodiazepine (BZ) site of GABA_A receptors, the underlying mechanisms for the behavioral effects of flavonoids are less understood.

Baicalin, a naturally occurring flavonoid, was previously reported to induce anxiolytic-like effect, devoid of sedation and myorelaxation, in mice through GABA_A receptors. The present study further expanded the behavioral pharmacology profile of baicalin, and subtype selectivity was explored as a possible mechanism underlying its in vivo effects. In the picrotoxin-induced seizure, step-through passive avoidance and rotarod tests, anticonvulsant, amnesic and motor incoordination effects commonly associated with classical BZs were not observed with baicalin at effective anxiolytic doses, demonstrating a separation of the anticonvulsant, amnesic and motor incoordination effects from anxiolytic-like effect. Moreover, baicalin showed significant preference to α₂- and α₃- containing subtypes compared with α₁- and α₅- containing subtypes in whole-cell patch clamp studies. Its subtype selectivity indicated that baicalin exerted anxiolytic-like effect mainly through the α₂- and α₃- containing subtypes, suggesting α₂- and α₃- containing subtypes were important drug targets for flavonoid-based anxiolytics.

In addition, 6,2’-dihydroxyflavone (DHF) was characterized for potential inverse agonistic activity, and its mechanism of action was explored for GABA_A receptor subtype selectivity. In electrophysiological studies on neuroblastoma IMR-32 cells, DHF decreased GABA-currents, which could be blocked by a BZ site antagonist. In mice behavioral models, DHF elicited significant anxiogenic-like effects in the elevated plus-maze test, and enhanced cognitive performance in the step-through passive avoidance test, while not exhibiting any proconvulsant effects. On recombinant GABA_A receptors, DHF decreased GABA-currents in α₁β₃γ₂, α₂β₃γ₂, or α₅β₃γ₂, but not α₃β₃γ₂ subtypes. The results demonstrated DHF as a partial inverse agonist of GABA_A receptors with selectivity in receptor subtypes as well as behavioral effects, extending the efficacy of flavonoids from agonists and antagonists to inverse agonists of GABA_A receptors. Moreover, the selective profile displayed in mice behavioral models supported DHF as a useful lead compound for the development of cognition-enhancing agents devoid of convulsion side effect.