K(+)-channel openers suppress epileptiform activities induced by 4-aminopyridine in cultured rat hippocampal neurons.

K(+) channels are key modulators of neuronal excitability, and mutations in certain types of these channels are known to cause epileptic seizures. Activation of K(+) channels is reported to suppress epileptic discharge; however, the types of K(+)-channel openers that are most effective as anti-epileptic agents are not well understood. We established a quantitative fluorescence assay using the Na(+) indicator sodium-binding benzofuran isophthalate (SBFI) for evaluation of various compounds on epileptiform activities induced by 4-aminopyridine (4-AP) in cultured rat hippocampal neurons. Among the K(+)-channel openers, the K(V)7.2/K(V)7.3-channel openers retigabine and flupirtine and K(Ca)2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the K(Ca)1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The K(ir)6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that K(V)7.2/K(V)7.3, K(Ca)2, and, to some extent, K(Ca)1.1-channel openers, but not K(ir)6-channel openers, suppress 4-AP-induced epileptiform activities in hippocampal neurons. These results suggest that the K(+)-channel openers for this category of K(+) channels might have therapeutic potential as new classes of antiepileptic drugs.