Effect of Na-K exchanger inhibitor bepridil on neuronal death -single fiber study-

Na-K交换抑制剂贝普地尔对神经元死亡的影响-单纤维研究-

• 批准号: 04670487
• 负责人: KAJI Ryuji
• 金额: $ 1.28万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670487/
• 关键词: single fiber; Na-Ca Exchanger; Na-K pump; K channel; conduction block; blood-nerve barrier; multifocal motor neuropathy; anti-GM1 antibody; Kチャネル; 抗GM1抗体; 単一神経線維; 虚血; 神経細胞死

Neuronal death is a consequence of abnormal Ca influx into the cell. This Ca influx is caused by reverse operation of Na-Ca exchanger, which normally excretes calcium in exchange of sodium out of the cell. Recent report suggested a protective effect of Na-K exchanger inhibitors on ischemic neuronal death through preventing the reverse operation (Stys 1991, Ann Neurol 30 : 375). We examined the effect of bepridil, a inhibitor, on the conduction disturbance in a single fiber recording caused by ischemia. Twelve Wistar rats were anesthetized with pentobarbital and had laminectomy over the lower thoracic and lumber spines. After cutting the dura, we made a pool of paraffin over the cauda equina and picked up ventral roots from the tail. A root was hung over a pair of microelectrocles to record a single fiber action potential by stimulating the tail(Figure below). After having made a stable recording, we ligated the proximal end of the root to produce ischemia. Recording were made every minutes, and the procedures were reproduced applying a normal saline or bepridil (0.1 M) over the entire distal stump of the root in order to observe their specific effects. All the 21 fibers treated with saline from 12 rats showed conduction failure by 32 minutes after ligation (mean 22.8(〕SY.+-.〔)4.1). There was however no significant difference between normal saline-treated group and bepridil-treated group (mean 21.1(〕SY.+-.〔)5.2, n=14). The present study did not reveal any beneficial effect of the Na-K exchanger in contrast to the previous reoprt (Stys et al 1991). The difference may be accounted for by two factors. First, ischemic conduction disturbance may be overshadowed by depolarization brought about through suppression of the sodium potassium pump, which normally hyperpolarizes the membrane. Second, bepridil may have other actions than inhibiting the exchanger. Whatever the reason may be, bepridil may not warrant its further clinical trials for ischemic nervous system disorders

神经元死亡是CA异常影响细胞的结果。这种CA的影响是由Na-Ca交换的反向操作引起的，NA-CA交换通常超过钙从细胞中交换。最近的报告表明，Na-K交换器抑制剂对缺血性神经元死亡具有防止反向操作的保护作用（Stys 1991，Ann Neurol 30：375）。我们检查了抑制剂Bepridil对缺血引起的单个纤维记录中传导干扰的影响。将十二只wistar大鼠用五骨骨麻醉，并在下胸和木质刺上进行椎板切除术。切开硬脑膜后，我们在尾部上制作了一块石蜡，并从尾部捡起腹部。一个根悬挂在一对微电磁上，通过刺激尾巴来记录单个纤维动作电位（下图）。制作稳定的记录后，我们将根的近端结合起来产生缺血。每分钟进行记录，并在根部的整个远端树桩上应用正常的盐水或Bepridil（0.1 m），以观察其特定效果。结扎后32分钟，用12只大鼠的盐水处理的所有21个纤维显示了传导失败（平均22.8（<sy。+ - 。<）4.1）。但是，正常生理盐水处理的组和BEPRIDIL治疗组之间没有显着差异（平均21.1（> sy。+ - 。。）5.2，n = 14）。本研究与先前的Reoprt相比，没有揭示Na-K交换器的任何有益作用（Stys等，1991）。差异可以由两个因素解释。首先，缺血传导障碍可能会因抑制钠泵而产生的沉积掩盖，钾泵通常使膜超极化。其次，除了抑制交换之外，贝普里迪尔可能还采取其他行动。不管是什么原因，Bepridil可能不保证其进一步的缺血性神经系统疾病的临床试验

项目成果

Hamano T,et al.: "Lack of prolonged cerebral blood flow change after transcranial magnestic stimulation." Electroenceph Clin Neurophysiol. 89. 207-210 (1993)

Hamano T 等人：“经颅磁刺激后缺乏长时间的脑血流变化。”

Kaji R,et al.: "Fasciculation evoked by cortical stimulation in amyotrophic lateral sclerosis." Ann Neurol. (in press). (1993)

Kaji R 等人：“肌萎缩侧索硬化症中皮质刺激引起的肌束颤动。”

Hamano T: "Lack of prolonged cerebral blood flow change after transcranial magnestic stimulation." Electroenceph Clin Neurophysiol. 89. 207-210 (1993)

Hamano T：“经颅磁刺激后缺乏长时间的脑血流变化。”

Kaji R,et al.: "Pathological findings at the site of conduction block in maltifocal motor neuropathy." Ann Neurol. 33. 152-158 (1993)

Kaji R 等人：“多灶性运动神经病传导阻滞部位的病理学发现。”

Hamano T: "Vivration-evoked sensory nerve action potentials derived from Paccinian corpuscles." Electroencephalogr Clin Neurophysiol. 89. 278-286 (1993)

Hamano T：“源自帕西尼小体的振动诱发的感觉神经动作电位。”