Alpha (α)-asarone, a major effective component isolated from the Chinese medicinal herb Acorus tatarinowii, is clinically used as medication for treating epilepsy, cough, bronchitis, and asthma. In the present study, we demonstrated that α-asarone targets central nervous system GABAA receptor as well as voltage-gated Na+ channels. Using whole-cell patch-clamp recording, α-asarone inhibited spontaneous firing of output neurons, mitral cells (MCs), in mouse olfactory bulb brain slice preparation and hyperpolarized the membrane potential of MCs. The inhibitory effect of α-asarone persisted in the presence of ionotropic glutamate receptor blockers but was eliminated after adding a GABAA receptor blocker, suggesting that GABAA receptors mediated the inhibition of MCs by α-asarone. This hypothesis was supported by the finding that α-asarone evoked an outward current, but did not influence inhibitory postsynaptic currents (IPSCs). In addition to inhibiting spontaneous firing, α-asarone also inhibited the Nav1.2 channel, a dominant rat brain Na+ channel subtype. The effects of α-asarone on a defined Nav1.2 were characterized using transfected cells that stably expressed the Nav1.2 channel isoform. α-Asarone displayed strong tonic inhibition of Nav1.2 currents in a concentration- and membrane potential-dependent fashion. α-Asarone reduced channel availability in steady-state inactivation protocols by enhancing or stabilizing Na+ channel inactivation. Both Na+ channel blockade and activation of GABAA receptors provide a possible mechanism for the known anti-epileptic effects of α-asarone. It also suggests that α-asarone could benefit patients with cough possibly through inhibiting a Na+ channel subtype to inhibit peripheral and/or central sensitization of cough reflexes.
Keywords: GABAA receptors, sodium channel blocker, α-asarone, central nerve Nav1.2 channel, olfactory bulb, anticonvulsant, sensitization of cough reflexes
Citation: Wang Z-J, Levinson SR, Sun L and Heinbockel T (2014) Identification of both GABAA receptors and voltage-activated Na+ channels as molecular targets of anticonvulsant α-asarone. Front. Pharmacol. 5:40. doi: 10.3389/fphar.2014.00040
Received: 13 November 2013; Accepted: 20 February 2014;
Published online: 11 March 2014.
Edited by:Lin-Hua Jiang, University of Leeds, UK
Reviewed by:David J. Adams, RMIT University, Australia
Copyright © 2014 Wang, Levinson, Sun and Heinbockel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ze-Jun Wang and Thomas Heinbockel, Department of Anatomy, College of Medicine, Howard University, 520 W Street North West, Washington, DC 20059, USA e-mail: firstname.lastname@example.org; email@example.com