Development and usefulness of aging model rat with epileptic seizures.

癫痫发作衰老模型大鼠的开发和用途。

• 批准号: 03455016
• 负责人: TAKAORI Shuji
• 金额: $ 3.46万
• 依托单位: Shimane Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03455016/
• 关键词: Aging model rat; Spontaneously epileptic rat; Autoradiography; Muscarinic cholinergic receptor; TRH related analog; Hippocampus; Cerebral arteries; L-arginine; CNK-602A; 尾状核; 海馬CA3錐体ニューロン; 脳血管; レ-ザ-ドップラ-血流計; オ-トラジオグラフ; ムスカリン性アセチルコリン受容体; GAB

Spontaneously epileptic rat (SER) is a genetically defined double mutant (zi/zi, tm/tm) obtained by mating the tremor heterozygous rat with the zitter homozygous rat, and exhibits both absence-like and tonic seizures without external stimuli or when mildly stimulated by tapping and sound. Computer analysis using quantitative autoradiographic technique revealed that the amount of the specific binding of (^3H)QNB to muscarinic cholinergic (mACh) receptors in the striatum of SER was more than that of control animals. However, the specific bindings to GABA_A and phencyclidine receptors of SER were not different from those of controls. These results suggested that hyperfunction of mACh receptors was involved in the appearance of seizures of SER. When a single stimulus was applied to the mossy fibers, there was repetitive firing and a depolarization shift in the hippocampal CA3 pyramidal neurons of the mature SER, in which seizures had fully developed. However, in young SER and littermates, which did not show any seizures, only a single spike was elicited with each single stimulation of the mossy fibers. These results indicated that CA3 pyramidal neurons of the SER became abnormally excitable in conjunction with the development of seizures. In the SER, a novel throtropin-releasing hormone (TRH) related analog, CNK-602A, suppressed absence-like and tonic seizures in a dose-dependent manner, and the inhibitory effects of the drug on both seizures were antagonized by pretreatment with haloperidol. CNK-602A increased the release of dopamine in the brain. The antiepileptic effects of CNK-602A were more potent and lasted longer than those of TRH. Furthermore, we showed that L-arginine was a physiological precursor for the formation of nitric oxide in the large cerebral arteries.

自发性癫痫大鼠(SER)是由震颤杂合大鼠与Zitter纯合子大鼠交配而获得的一种双重突变体(zi/zi，tm/tm)，在没有外界刺激或受到敲击和声音轻微刺激的情况下，同时表现出失神和紧张性发作。计算机定量放射自显影分析表明，SER动物纹状体M胆碱能(MACH)受体与(~3H)QNB的特异性结合量高于对照组动物。然而，SER与GABA_A和苯环利定受体的特异性结合与对照组无明显差异。提示马赫受体功能亢进参与了SER惊厥的发生。单次刺激苔藓纤维后，成熟SER组大鼠海马CA3区锥体神经元出现重复放电和去极化位移，癫痫发作已完全形成。然而，在没有表现出任何癫痫发作的年轻SER和产仔鼠中，每次刺激苔藓纤维只诱导出一个单一的棘波。这些结果表明，随着癫痫的发展，SER的CA3锥体神经元变得异常兴奋。在SER中，一种新的促甲状腺激素释放激素(TRH)类似物CNK-602a以剂量依赖的方式抑制失神样发作和强直性发作，该药对这两种发作的抑制作用可被氟哌啶醇预处理所拮抗。CNK-602A增加了脑内多巴胺的释放。CNK-602a的抗癫痫作用比TRH更强，持续时间更长。此外，我们还发现，L-精氨酸是大脑大动脉一氧化氮形成的生理前体。

项目成果

Yoshimura N: "Dopamine D-1 receptor-mediated inhibition of micturition reflex by central dopamine from the substantia nigra." Neurourol Urodynamics. 11. 535-545 (1992)

Yoshimura N：“多巴胺 D-1 受体介导的黑质中枢多巴胺对排尿反射的抑制。”

Murase K: "Characteristics of muscarinic cholinergic, γ-aminobutyric acidA and phencyclidine receptors in SER; autoradiographic analysis." Neurosci Lett. 131. 1-4 (1991)

Murase K：“SER 中毒蕈碱胆碱能、γ-氨基丁酸 A 和苯环己哌啶受体的特征；放射自显影分析。”Neurosci Lett。

Ishihara K: "Abnormal excitability of hippocampal CA3 pyramidal neurons of spontaneously epileptic rat (SER),a double mutant." Exp Neurol.

Ishihara K：“自发性癫痫大鼠 (SER) 海马 CA3 锥体神经元的异常兴奋性，双突变体。”

Xie R: "Antiepileptic effects of CNK-602A, a novel thyrotropinreleasing hormone analog,on absence-like and tonic seizures of SER." Eur J Pharmacol. 223. 185-192 (1992)

谢锐：“CNK-602A（一种新型促甲状腺激素释放激素类似物）对 SER 的失神样癫痫发作和强直性癫痫发作具有抗癫痫作用。”

Ishihara K: "Abnormal excitability of hippocampal CA3 pyramidal neurons of spontaneously epileptic rat (SER), a double mutant." Exp Neurol.

Ishihara K：“自发性癫痫大鼠 (SER) 海马 CA3 锥体神经元的异常兴奋性，双突变体。”