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

• Project/Area Number: 13557069
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 展開研究
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: IINUMA Kazuie Department of Pediatrics, Professor, 大学院・医学系研究科, 教授 (80004927)
• Co-Investigator(Kenkyū-buntansha): MUNAKATA Mitsutoshi Department of Pediatrics, Research Associate, 医学部附属病院, 助手 (30312573) ; YOKOYAMA Hiroyuki Department of Pediatrics, Research Associate, 医学部附属病院, 助手 (40271952) ; HAGINOYA Kazuhiro Department of Pediatrics, Associate Professor, 大学院・医学系研究科, 助教授 (00208414) ; MASUDA Yoshinobu Dainippon Pharmaceutical Co., Chief Researcher, 創薬研究所, 主任研究員
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥6,600,000 (Direct Cost: ¥6,600,000); Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2001: ¥4,900,000 (Direct Cost: ¥4,900,000)
• Keywords: 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

Research Abstract

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.

Research Products

• [Publications] Chen Z., Li Z., Sakurai E., Mobarakeh J.I., Ohtsu H., Watanabe T., Iinuma K., Yanai K.: "Chemical kindling induced by pentylenetetrazol in histamine H1 receptor gene knockout mice (H1KO), histidine decarboxylase-deficient mice (HDC-/-) and mast cell-deficient W/Wv mice"Brain Res.. 968. 162-166 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Chen Z., Sakurai E., Mobarakeh J.I., Ohtsu H., Watanabe T., inuma K., Yanai K.: "Chemical kindling induced by pentylenetetrazol in histamine H1 receptor gene knockout mice (H1KO), histidine deceboxylase-deficient mice (HDC-/-) and mast cell-deficient W/Wv mice."Brain Res.. 968. 62-166 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Iinuma K., Yokoyama H: "Schmnidt D, Schachter SC"110 Puzzling Cases of Epilepsy. 316-319 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Chen Z., Li Z., Sakurai E., Mobarakeh J.I., Ohtsu H., Watanabe T., inuma K., Yanai K.: "Chemical kindling induced by pentylenetetrazol in histamine H1 receptor gene knockout mice (H1KO), histidine decarboxylase-deficient mice (HDC-/-) and mast cell-deficient W/Wv mice"Brain Res.. (In press). (2003)