The Study of Cholinergic Nerve Disfunction induced by AF64A.

AF64A所致胆碱能神经功能障碍的研究。

• 批准号: 61560346
• 负责人: YAGASAKI Osamu
• 金额: $ 0.77万
• 依托单位: University of Osaka Prefecture, College of Africulture,
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1986
• 资助国家: 日本
• 起止时间: 1986 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-61560346/
• 关键词: Ethylcholinemustard; Cholinergic nervous system; Acetylcholine release choline uptake; intestinal motility; 腸運動; デルドリン痙攣; AF64A; 神経機能障害; 腦; 小腸

General toxicity:Rat injected i.p. with AF64A at a dose of 1/3 to 11/25 LD50 (291 umol/kg) showed a transient sign of motor disterbance and long lasting singns of adipsia and aghagia. When rats received AF64A with an initial dose of 86 umol/kg i.p. and nine consecutive daily dose of 12.9 umol/kg, ACh contents in the cerebral cortex, hippocampus and striatum decreased significantly. The decrease was sustained even 10 days after the last injection. ACh release induced by electrical stimulation or high K^+ was significantly reduced. The T-maze spontaneous alternation behavior in the treated rats was also impaired. The levels of other neurotransmitters such as NE, 5-HT and GABA were unchanged. No morphological changes in the brain was detected by light- or electron-microscopic observations.Neurochemical observations:Administration of choline with AF64A significantly inhibited the development of the signs of the functional deficienty of central cholinergic nervous system in rats. In the AF6 … More 4A treated rats, ChAT activity in nerve terminals decreased in hippocampus and cortex, while the agent had no direct effect on the extracted soluble ChAT. The brain synaptosomal preparations from AF64A treated rat had the same activity of high affnity choline uptake with that of control. A specific binding of [^3H]nicotine to membrane preparation from cortex increases. These results further support a presynaptic site of aciton for AF64A, and suggest that it may acutely disrupt some processes underlying ACh release.Applications:In AF64A treated mice, the neurotoxic symptoms evoked by dieldrin were clearly alleviated supporting our previous suggestion that excitatory cholinergic mechanism in CNS may be involved in the neurotoxic symptoms. In another series of experiments, half of intestines form AF64A treated rats failed to produce the relaxations of the circular muscles in the anal part of locally distended wall of the intestine. These results suggest that there exist cholinergic interneurons in the nervous pathways from the mechano-receptors to the smooth muscles.Conclusion: AF64A is an usuful agent in studying the physiological roles of cholinergic nervous systems. Less

一般毒性：大鼠按1/3 ~ 11/25 LD50 （291 umol/kg）剂量ig注射AF64A，出现短暂性运动障碍和长时间的失食和失语症状。当AF64A初始剂量为86 umol/kg，连续9天剂量为12.9 umol/kg时，大鼠大脑皮层、海马和纹状体中乙酰胆碱含量显著降低。即使在最后一次注射后10天，这种下降仍在持续。电刺激或高K^+诱导的乙酰胆碱释放明显减少。治疗后大鼠的T-maze自发交替行为也受到损害。其他神经递质如NE、5-羟色胺和GABA的水平没有变化。通过光镜或电子显微镜观察，没有发现大脑的形态学变化。神经化学观察：胆碱与AF64A联合用药可显著抑制大鼠中枢胆碱能神经系统功能缺陷体征的发生。AF6…More 4A处理大鼠海马和皮质神经末梢ChAT活性降低，但对提取的可溶性ChAT无直接影响。AF64A处理的大鼠脑突触体制剂具有与对照组相同的高亲和胆碱摄取活性。[^3H]尼古丁与皮层膜制剂的特异性结合增加。这些结果进一步支持了AF64A的突触前作用位点，并表明它可能严重破坏一些潜在的乙酰胆碱释放过程。应用：在AF64A处理的小鼠中，狄氏剂引起的神经毒性症状明显减轻，这支持了我们之前提出的中枢神经系统兴奋性胆碱能机制可能参与神经毒性症状的观点。在另一组实验中，半数经AF64A处理的大鼠肠道不能产生局部膨胀肠壁肛门部分的环形肌肉松弛。这些结果表明，从机械受体到平滑肌的神经通路中存在胆碱能中间神经元。结论：AF64A是研究胆碱能神经系统生理作用的有用药物。少

项目成果

Morio,Y. ; Yagasaki,O.: "Neurotoxic symptoms by DDT and dieldrin in AF64A treated rats -- Cholinergic contribution to the toxic symptomes."

森里奥，Y.

矢ケ崎修,辻浩美: 日平滑筋誌. 22. 210-213 (1986)

Osamu Yagasaki，Hiromi Tsuji：日本平滑肌杂志 22. 210-213 (1986)。

Nishio,H.;Noda,A.;Morio,Y. ; Yagasaki,O.: "Effects of ethylcholine mustard aziridinium ion (AF64A) administered intraperitoneally on cholinergic nerves in rat brain." Folia Pharmacol. Japon.92. (1988)

西尾，H.；野田，A.；森里奥，Y.

Yagasaki,O. ; Tsuji,H.: "The study of anal relexation of circular muscle in rat isolated small intestine." J. Smooth Muscle Res.22. 210-213 (1986)

矢崎，O.

矢ケ崎修: 日平滑筋誌. 22. 210-213 (1986)

Osamu Yagasaki：日本平滑肌杂志 22. 210-213 (1986)。