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

神经元死亡是异常Ca流入细胞的结果。这种Ca内流是由Na-Ca交换器的反向操作引起的，Na-Ca交换器通常将钙排出细胞以交换钠。最近的报道表明，Na-K交换抑制剂通过防止逆转作用对缺血性神经元死亡具有保护作用（Stys 1991，Ann Neurol 30：375）。我们研究了苄普地尔，一种抑制剂，对缺血引起的单纤维记录传导障碍的影响。12只Wistar大鼠用戊巴比妥麻醉，并在下胸椎和腰椎上进行椎板切除术。切开硬脑膜后，我们在马尾上做了一个石蜡池，并从尾部取出腹根。将一根悬在一对微电极上，通过刺激尾部记录单纤维动作电位（下图）。记录稳定后，结扎牙根近端造成缺血。每分钟记录一次，并在牙根的整个远端残端上应用生理盐水或苄普地尔（0.1M）重复该过程，以观察其具体效果。12只大鼠用生理盐水处理的21根纤维在结扎后32分钟全部出现传导障碍（平均22.8 ± 0.5SY）。（）4.1）。但生理盐水治疗组和苄普地尔治疗组之间无显著差异（平均21.1 ± 0.05 SY）。()5.2，n=14）。与之前的报告（Stys等，1991）相比，本研究未显示Na-K交换剂的任何有益作用。这种差异可以由两个因素来解释。首先，缺血性传导障碍可能被钠钾泵抑制引起的去极化所掩盖，钠钾泵通常使膜超极化。第二，苄普地尔可能具有抑制交换剂以外的其他作用。不管是什么原因，苄普地尔可能不值得进一步的缺血性神经系统疾病的临床试验

项目成果

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.: "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,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: "Anti-GM1 Antibodies and Impaired Blood-Nerve Barrier May Interfere with Remyelination in Multifocal Motor Neuropathy." Muscle Nerve. 17. 108-110 (1994)

Kaji R：“抗 GM1 抗体和受损的血神经屏障可能会干扰多灶性运动神经病的髓鞘再生。”

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。”