Antidepressant, anticonvulsant and antinociceptive effects of 3′-methoxy-6-methylflavone and 3′-hydroxy-6-methylflavone may involve GABAergic mechanisms

Abstract

GABAA receptors have been implicated in the pathophysiology of depression, epilepsy and pain disorders. The purpose of this study was to investigate two novel synthetic flavones, 3'-methoxy-6-methylflavone (3'-MeO6MF) and 3'-hydroxy-6-methylflavone (3'-OH6MF), for their effect on GABAA receptors and subsequently investigate their antidepressant, anticonvulsant and antinociceptive effects. Recombinant GABAA receptor subunits were expressed in Xenopus oocytes and a two electrode voltage clamp technique was used for electrophysiological studies. The antidepressant and anticonvulsant activities were determined using forced swim (FST) and tail suspension tests (TST) and bicuculline (BIC)-induced seizures respectively. Furthermore, the antinociceptive activity was determined using tail immersion and hot plate tests. 3'-MeO6MF and 3'-OH6MF potentiated GABA-induced currents through ternary α1-2β1-3γ2L and binary α1β2 receptors indicating that the positive modulation by these flavonoids is not dependent on the γ subunit. In behavioral studies, 3'-MeO6MF and 3'-OH6MF (10-100mg/kg, ip) exerted significant antidepressant like effects in the FST and TST. 3'-MeO6MF (10-100mg/kg) and 3'-OH6MF (30 and 100mg/kg) also exhibited significant anticonvulsant effects in BIC-induced seizures, and antinociceptive activity in tail immersion and hot plate tests (*p<0.05, **p<0.01, ***p<0.001). Furthermore, the antidepressant and antinociceptive activities of 3'-MeO6MF and 3'-OH6MF were partially ameliorated by co-administration of BIC (3mg/kg) suggesting the involvement of GABAergic mechanisms. The findings of this study suggest that 3'-MeO6MF and 3'-OH6MF exhibited significant antidepressant, anticonvulsant and antinociceptive effects mediated via interactions with GABAA receptors.