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

Nasiara Karim; Imran Khan; Naveed Ahmad; Muhammad Naveed Umar; Navnath Gavande

doi:10.1016/j.pharep.2017.03.001

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

Pharmacol Rep. 2017 Oct;69(5):1014-1020. doi: 10.1016/j.pharep.2017.03.001. Epub 2017 Mar 10.

Authors

Nasiara Karim¹, Imran Khan², Naveed Ahmad³, Muhammad Naveed Umar⁴, Navnath Gavande⁵

Affiliations

¹ Department of Pharmacy, University of Malakand, Chakdara, Dir (Lower), KPK, Pakistan. Electronic address: nasiara.karim@hotmail.com.
² Department of Pharmacy, University of Swabi, KPK, Pakistan.
³ Department of Pharmacy, University of Malakand, Chakdara, Dir (Lower), KPK, Pakistan.
⁴ Department of Chemistry, University of Malakand, Chakdara, Dir (Lower), KPK, Pakistan.
⁵ Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.

PMID: 28943291
DOI: 10.1016/j.pharep.2017.03.001

Abstract

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

Methods: Recombinant GABA_A 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_A receptors.

Keywords: Bicuculline; Flavonoids; Forced swim test; GABA(A) receptors; Hot plate test; Xenopus oocytes.

MeSH terms

Analgesics / administration & dosage
Analgesics / chemistry
Analgesics / pharmacology*
Animals
Anticonvulsants / administration & dosage
Anticonvulsants / chemistry
Anticonvulsants / pharmacology*
Antidepressive Agents / administration & dosage
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology*
Dose-Response Relationship, Drug
Flavones / administration & dosage
Flavones / chemistry
Flavones / pharmacology*
GABA Agents
Male
Mice
Molecular Structure
Nociception
Pain Measurement / drug effects
Receptors, GABA-A / metabolism
Tramadol / pharmacology

Substances

Analgesics
Anticonvulsants
Antidepressive Agents
Flavones
GABA Agents
Receptors, GABA-A
Tramadol