Abstract
Background
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.
Methods
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.
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 (10–100 mg/kg, ip) exerted significant antidepressant like effects in the FST and TST. 3′-MeO6MF (10–100 mg/kg) and 3′-OH6MF (30 and 100 mg/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 (3 mg/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 GABAA receptors.
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Karim, N., Khan, I., Ahmad, N. et al. Antidepressant, anticonvulsant and antinociceptive effects of 3′-methoxy-6-methylflavone and 3′-hydroxy-6-methylflavone may involve GABAergic mechanisms. Pharmacol. Rep 69, 1014–1020 (2017). https://doi.org/10.1016/j.pharep.2017.03.001
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DOI: https://doi.org/10.1016/j.pharep.2017.03.001