K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

• Published in: Journal of Pharmacological Sciences Vol. 108; no. 4; pp. 517 - 528
• Main Authors: Kobayashi, Kiyoaki, Nishizawa, Yukio, Sawada, Kohei, Ogura, Hiroo, Miyabe, Masayuki
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2008; The Japanese Pharmacological Society; Elsevier
• Subjects: 4-Aminopyridine; 4-aminopyridine (4-AP); Animals; Anticonvulsants - pharmacology; Benzofurans; Cells, Cultured; epilepsy; Epilepsy - drug therapy; Epilepsy - physiopathology; Ethers, Cyclic; Fluorescence; Fluorescent Dyes; hippocampal neuron; Hippocampus - cytology; Hippocampus - drug effects; K+ channel; Neurons - drug effects; Neurons - metabolism; Potassium Channels - drug effects; Potassium Channels - metabolism; Rats; Rats, Wistar; sodium-binding benzofuran isophthalate (SBFI); K+ channel; epilepsy; sodium-binding benzofuran isophthalate (SBFI); 4-aminopyridine (4-AP); hippocampal neuron
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.08214FP

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 KV7.2/KV7.3-channel openers retigabine and flupirtine and KCa2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the KCa1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The Kir6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that KV7.2/KV7.3, KCa2, and, to some extent, KCa1.1-channel openers, but not Kir6-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.