Stability of nNOS in generalized epilepsy

本研究的主要目的是阐明一氧化氮依赖与广泛性癫痫的关系。采用戊四唑（PTZ）作为小鼠全身性癫痫动物模型。PTZ的日常管理与nNOS和NO生产的数量和活动的增加有关。为了证实nNOS与NO之间的关系，我们用缺失nNOS基因的小鼠（nNOS-/-小鼠）观察PTZ点火的发展。nNOS-/-小鼠在注射PTZ （40 mg/kg）和PTZ （30 mg/kg）点燃过程中表现出更严重的癫痫发作。因此，行为学证据表明，nNOS可能与ptz诱导的小鼠癫痫发作有关，而与ptz诱导的点燃的发生无关。为了证实PTZ对nNOS-/-小鼠的敏感性增加，我们用nNOS抑制剂TRIM（1-（2-三氟甲基苯基）咪唑）治疗野生型（nNOS+/+）小鼠，并测量尺寸评分。经TRIM处理的nNOS+/+小鼠呈剂量依赖性增强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，这些结果表明，谷氨酸能神经元的正常激活可能受NO基础活性的调节。另一方面，PTZ对谷氨酸能神经元的过度激活可能由NMDAR激活nNOS合成的NO加速。

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.