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
V7.2/K
V7.3-channel openers retigabine and flupirtine and K
Ca2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the K
Ca1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The K
ir6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that K
V7.2/K
V7.3, K
Ca2, and, to some extent, K
Ca1.1-channel openers, but not K
ir6-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.
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