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

脑组胺似乎参与了癫痫易感性的调节机制，组胺的抗惊厥作用已被证实。这种抗惊厥作用被认为是通过组胺H1受体介导的。组胺受体包括突触后H1和H2受体，以及调节组胺释放的突触前H3受体。组胺与H3受体的结合抑制了组胺的释放。组胺H3受体拮抗剂可能通过增加组胺释放而抑制癫痫发作。我们通过戊四氮点燃模型评价了内源性组胺对癫痫发作的抑制作用。侧脑室注射H3受体拮抗剂氯苯丙特可延长点燃完成时间。此作用可被H3受体激动剂immepip和HDC抑制剂FMH所抑制。FMH和吡咯胺均能抑制点燃的发展。这一发现表明，内源性组胺通过H1和H3受体抑制惊厥。我们还创造了缺乏组胺H3受体的小鼠。这些小鼠表现出普遍的运动能力低下和体温下降，但保持了昼夜节律。硫代巴比妥钠，H3受体拮抗剂，对催醒作用不敏感。证实H3受体对觉醒反应有一定的作用。

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.