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Stability of nNOS in generalized epilepsy

全身性癫痫中 nNOS 的稳定性

基本信息

批准号：
17590081
负责人：
ITOH Kouichi
金额：
$ 2.24万
依托单位：
Tokushima Bunri University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590081/
关键词：
NO NOS inhibitors Epilepsy Proteosome nNOS PTZ Neural Cell Adhesion Molecules NOS阻害キンドリングユビキチン

项目摘要

The major aim of this study was to elucidate relationship between NOS-dependent NO and generalized epilepsy. Pentylenetetrazole (PTZ) was used to induce kindling in mouse as animal model of generalized epilepsy. The daily administration of PTZ is associated with increases in the amount and activities of nNOS and NO production. To confirm the relationship between nNOS and NO, mice lacking nNOS gene (nNOS-/-mice) were used to observe the development of PTZ kindling. nNOS-/-mice exhibited more severe seizures following injection with PTZ (40 mg/kg) and during the development of PTZ (30 mg/kg) kindling. Thus, the behavioral evidence indicated that nNOS might be related to PTZ-induced seizures in mice, but not to the development of PTZ-induced kindling.To confirm the increase in sensitivity of PTZ in nNOS-/-mice, wild type (nNOS+/+) mice were treated with nNOS inhibitor, TRIM (1-(2-trifluoromethylphenyl)imidazole) and measured sizure scores. The nNOS+/+ mouse treated with TRIM were dose-dependently enhanced PTZ-induced tonic-clonic convulsions. The enhancement of tonic-clonic convulsions by TRIM was coincident with the increase in sensitivity of PTZ in nNOS-/-mice. Therefore, these results suggest that the normal activation of glutamatergic neurons could be regulated by basal activity of NO. On the other hand, the overactivation of glutamatergic neurons by PTZ might be accelerated by NO which was synthesized by the activation of nNOS through NMDAR.

本研究的主要目的是阐明NOS依赖的NO与全身性癫痫的关系。采用戊四氮（PTZ）点燃小鼠作为全身性癫痫动物模型。PTZ的每日给药与nNOS和NO产生的量和活性的增加相关。为探讨nNOS与NO的关系，采用nNOS基因缺失小鼠（nNOS-/-mice）观察戊四氮（PTZ）点燃过程。nNOS-/-小鼠在注射PTZ（40 mg/kg）后和PTZ（30 mg/kg）点燃发展期间表现出更严重的癫痫发作。为了证实nNOS-/-小鼠中PTZ敏感性的增加，用nNOS抑制剂TRIM（1-（2-trifluoromethylphenyl）imidazole）处理野生型（nNOS+/+）小鼠并测量尺寸评分。TRIM处理的nNOS+/+小鼠剂量依赖性地增强PTZ诱导的强直-阵挛性惊厥。TRIM对nNOS-/-小鼠强直-阵挛性惊厥的增强与PTZ敏感性的增加一致。因此，NO的基础活性可调节多巴胺能神经元的正常激活，而NMDAR激活nNOS合成的NO可加速PTZ对多巴胺能神经元的过度激活。