The anticonvulsant retigabine is a subtype selective modulator of GABA_A receptors

Abstract

SummaryObjectiveWithin its range of therapeutic plasma concentrations, the anticonvulsant retigabine (ezogabine) is believed to selectively act on Kv7 channels. Here, the contribution of specific γ‐aminobutyric acid (GABA)A receptor subtypes to the antiseizure effects of retigabine was investigated.MethodsUsing patch‐clamp recordings, seizure‐like activity, tonic currents, and GABA‐induced currents in hippocampal neurons were tested for their sensitivity toward retigabine, as were recombinant GABA A receptors expressed in tsA 201 cells.ResultsRetigabine reduced seizure‐like activity elicited by low Mg2+ in a concentration‐dependent manner with half maximal inhibition at 1 μm. Seizure‐like activity triggered by blocking either Kv7 channels or GABA A receptors was equally reduced by retigabine, but when these channels/receptors were blocked simultaneously, the inhibition was lost. Retigabine (10 μm) enhanced bicuculline‐sensitive tonic currents in hippocampal neurons, but failed to affect GABA‐evoked currents. However, when receptors involved in phasic GABAergic inhibition were blocked by penicillin, retigabine did enhance GABA‐evoked currents. In tsA 201 cells expressing various combinations of GABA A receptor subunits, 10 μm retigabine enhanced currents through α1β2δ, α4β2δ, α4β3δ, and α6β2δ receptors, but left currents through α1β2γ2S, α4β3γ2S, α5β3γ2S, and α6β2γ2S receptors unaltered. With αβ receptors, retigabine diminished currents through α1β2 and α4β3, but increased currents through α6β2 receptors. The enhancement of currents through α1β2δ receptors by retigabine was concentration dependent and became significant at 1 μm.SignificanceThese results demonstrate that retigabine is a subtype selective modulator of GABA A receptors with preference for extrasynaptic δ‐containing receptors; this property may contribute to its broad antiepileptic effectiveness and explain its lack of effect on absence seizures.

Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet

“…At high concentrations (.10 mM), ezogabine was shown to potentiate GABA-mediated inhibitory transmission by acting as a positive allosteric modulator of GABA A receptors (Rundfeldt and Netzer 2000;Otto et al 2002). Recent evidence that inhibitory effects of the drug on seizure-like activity in hippocampal neurons persist in the presence of blockade of K v 7 channels has bolstered the view that positive modulation of GABA A receptors could be key to its antiseizure activity (Treven et al 2015). Thus, at lower concentrations than are required for effects on synaptic GABA A receptors, ezogabine selectively enhances extrasynaptic GABA A receptors that contain the d-subunit (Treven et al 2015).…”

“…Recent evidence that inhibitory effects of the drug on seizure-like activity in hippocampal neurons persist in the presence of blockade of K v 7 channels has bolstered the view that positive modulation of GABA A receptors could be key to its antiseizure activity (Treven et al 2015). Thus, at lower concentrations than are required for effects on synaptic GABA A receptors, ezogabine selectively enhances extrasynaptic GABA A receptors that contain the d-subunit (Treven et al 2015). Ezogabine has also been reported to increase GABA synthesis (Kapetanovic et al 1995); the mecha-nism and implications of this effect are not known.…”

KCNQ2/3 channel agonist flupirtine reduces cocaine place preference in rats

“…Furthermore, FLU by itself did not produce a compartmental shift. In this context, the most likely explanation for the efficacy of FLU is inhibition of cocaine reward, though anxiolytic effects cannot be excluded due to its GABA-enhancing activity (Treven et al, 2015). …”

Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis

“…RTG with its unique and selective M-current potassium channel opener properties makes neuronal membranes hyperpolarized and additionally, it selectively modulates extra-synaptic GABA A receptors with δ-subunit [8,9]. …”