Research for development of new antiepileptic drug with wake-promoting effect

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Brain histamine seems to be involved in the mechanism regulating seizure susceptibility, and a possible anticonvulsant action of histamine has been demonstrated. This anticonvulsant action has been considered to be mediated through histamine H1 receptors. The histamine receptors consist of postsynaptic H1 and H2 receptors, and presynaptic H3 receptor whick regulates the release of histamine. Histamine release is suppressed by binding of histamine to the H3 receptors. Then the histamine H3 receptor antagonist may inhibit seizures by in crease of histamine release.We evaluated whether intrinsic histamine inhibit seizures by using pentylentetrazol kindling model in rats. The duration of completion of kindling was prolonged by intraventricular injection of clobenpropit, H3 receptor antagonist. This effect was inhibited by immepip, H3 receptor agonist and both FMH, inhibiter of HDC. Both FMH and pyrilamine inhibited the development of kindling. This finding suggests that the intrinsic histamine affects to inhibit convulsion through H1 and H3 receptors.We also created mice lacking histamine H3 receptors. These mice showed generalized hypomotility and decreased body temperature, however maintained circadian rhythms. Thioperamide, H3 receptor antagonist induced insensitivity to wake-promoting effects. It was confirmed that H3 receptor had an effectiveness to waking reaction.