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

Background: GABA 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 GABA receptors and subsequently investigate their antidepressant, anticonvulsant and antinociceptive effects.

Methods: Recombinant GABA 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.

Results: 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.

Conclusion: The findings of this study suggest that 3'-MeO6MF and 3'-OH6MF exhibited significant antidepressant, anticonvulsant and antinociceptive effects mediated via interactions with GABA receptors.