Moderate concentrations of 4-O-methylhonokiol potentiate GABAA receptor currents stronger than honokiol

• We assessed potentiation of GABAA receptor currents by honokiol and 3-O-methylhonokiol.
• We found 3-O-methylhonokiol to be much more potent than honokiol.
• The γ subunit is not needed for the potentiation of GABAA receptor response.
• Potentiation is sensitive to isoforms of the α and β subunits of GABAA receptors.

BackgroundMagnolia bark preparations from Magnolia officinalis of Asian medicinal systems are known for their muscle relaxant effect and anticonvulsant activity. These CNS related effects are ascribed to the presence of the biphenyl-type neolignans honokiol and magnolol that exert a potentiating effect on GABAA receptors. 4-O-methylhonokiol isolated from seeds of the North-American M. grandiflora was compared to honokiol for its activity to potentiate GABAA receptors and its GABAA receptor subtype-specificity was established.MethodsDifferent recombinant GABAA receptors were functionally expressed in Xenopus oocytes and electrophysiological techniques were used determine to their modulation by 4-O-methylhonokiol.Results3 μM 4-O-methylhonokiol is shown here to potentiate responses of the α1β2γ2 GABAA receptor about 20-fold stronger than the same concentration of honokiol. In the present study potentiation by 4-O-methylhonokiol is also detailed for 12 GABAA receptor subtypes to assess GABAA receptor subunits that are responsible for the potentiating effect.ConclusionThe much higher potentiation of GABAA receptors at identical concentrations of 4-O-methylhonokiol as compared to honokiol parallels previous observations made in other systems of potentiated pharmacological activity of 4-O-methylhonokiol over honokiol.General significanceThe results point to the use of 4-O-methylhonokiol as a lead for GABAA receptor potentiation and corroborate the use of M. grandiflora seeds against convulsions in Mexican folk medicine.