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

具有促醒作用的新型抗癫痫药物的开发研究

基本信息

批准号：
13557069
负责人：
IINUMA Kazuie
金额：
$ 4.22万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557069/
关键词：
central histamine histamine H1 receptor histamine H3 receptor convulsion intrinsic histamine histamine H3 receptor antagonist waking reaction キンドリングペンチレンテトラゾール thioperamide

项目摘要

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.

脑组织胺似乎参与了癫痫发作易感性的调节机制，并已证明了组织胺可能的抗惊厥作用。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。组胺释放通过组胺与H3受体结合而被抑制。组胺H_3受体拮抗剂可能通过增加组胺的释放而抑制癫痫发作。侧脑室注射H3受体拮抗剂Clobenpropit可延长点燃完成时间。H3受体激动剂immepip和HDC抑制剂FMH均能抑制这种作用。FMH和吡拉明均抑制点燃的发展。这一发现表明，内源性组胺通过H1和H3受体抑制惊厥。我们还建立了缺乏组胺H3受体的小鼠。这些小鼠表现出全身性运动功能减退和体温降低，但维持昼夜节律。H3受体拮抗剂硫代哌丁胺对促醒作用不敏感。证实了H3受体对清醒反应的有效性。