Antiepileptic activity and subtype-selective action of flupirtine at GABAAreceptors

Abstract

Results In hippocampal neurons, flupirtine reduced seizure-like activity with no effect at 1 to 3 μM, and maximal effects at 10 to 30 μM; it enhanced currents through KV7 channels with EC50 values at 6 μM. Flupirtine (30 μM) modulated GABA-induced currents in hippocampal neurons by reducing EC50 values for GABA threefold and maximal current amplitudes by 15%. Hence, flupirtine acted as an uncompetitive antagonist. Flupirtine did not alter rise time, decay time, or amplitudes of miniature inhibitory postsynaptic currents (mIPSCs), but enhanced the bicuculline-sensitive tonic current. When phasic GABAergic inhibition was blocked by penicillin G (5 mM), flupirtine enhanced maximal amplitudes of GABA-evoked currents by 43%, but hardly affected EC50 values. As these results suggested that flupirtine was able to differentiate between different GABAA receptor subtypes, its effects on recombinant GABAA receptors were investigated in tsA cells. With a1b2g2 receptors, flupirtine reduced EC50 values for GABA threefold and maximal current amplitudes by 25%; with a1b2 receptors, it reduced EC50 values for GABA twofold, but reduced maximal current amplitudes by 35%.