Effect of Digitalis in Demyelinative Neurological Diseases and Their Animal Models : a Clinical and Electrophysiological Study

洋地黄对脱髓鞘性神经疾病及其动物模型的影响：临床和电生理学研究

• 批准号: 01440096
• 负责人: KIMURA Jun
• 金额: $ 2.56万
• 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 (A)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01440096/
• 关键词: Multiple Sclerosis; Digitalis; Neural Coding; Conduction Block; Demyelination; ウアバイン; シナプス再構成; rateーdependent block; ナトリウムーカリウム ポンプ; 動物モデル

1) We investigated the effect of digitalis (cardiac glycosides) on conduction in demyelinated nerve fibers. Digitalis, a blocker of the electrogenic Na/K pump, has been shown to prevent hyperpolarization of the axonal membrane and our preliminary evidence suggested that digitalis overcomes the failure to transmit high-frequency impulses (rate-dependent block) due to hyperpolarization. Our data also suggested that digitalis partially reverses complete conduction blocks due to demyelination possibly by lowering the resting membrane potential. We performed a single fiber study in demyelinated rat ventral root fibers and a serial SEP study in rats with spinal cord demyelination after administration of digitalis, correlating with clinical signs.2) Many patients with MS have clinically silent plaques, and clinical recovery in MS is often too rapid to be caused by remyelination. Demyelinated fibers in MS seen to transmit impulses, which could be biologically-useful after recovery of symptoms. … More Based on our previous study (Kaji, Suzumura, Sumner, Brain (1988) 111 ; 675-694, Appendix 1) , which showed failure of CNS demyelinated fibers to transmit trains of impulses of as low as 50 Hz frequency (rate-dependent block) at the onset of symptoms and clinical recovery with persistent rate-dependent block, we put forward the following hypothesis on the physiological mechanism of remissions and relapses of symptoms in MS :Clinical symptoms in MS could be caused by rate-dependent block in the absence of complete conduction block because information is coded as frequencies of impulses utilizing high-frequency range (up to 250 Hz or more) in CNS fibers (frequency modulation). Clinical recovery is attained by adaptive processes of axon terminals and postsynaptic neurons leading to re-interpretation of the modified trains of impulses. Relapses of symptoms are brought about by slight extension of the plaque or any other factors that again lower the safety factor of transmission and in turn reduce the maximal frequency that demyelinated fibers can follow, rendering the information carried in the discharge pattern uninterpretable by the post-synaptic neuron.To test this hypothesis, we have established a model in which we can analyze coding of information in the dorsal column fibers and neurons in the gracile neuclei after vibratory stimulation on the foot pad in rats with spinal cord demyelination. Our preliminary study showed loss of information on the vibratory frequency caused by rate-dependent blocks due to demyelination (Kaji R, Kimura J, et al. Submitted to Brain). We clarified the mechanism of the recovery process by recording from demyelinated fibers (dorsal column) and postsynaptic neurons (gracile neurons) as well as ultrastructural andHRP studies in the gracile nucleus. We also examined the effect of digitalis on the impaired neural coding in this model, specifically its ability to reverses rate-dependent block.3) Based on the above animal experiments, we examined the effect of intravenous digoxin on clinical symptoms and evoked potential parameters in patients with multiple sclerosis. Digoxin, a digitalis derivative, could successfully reverse the clinical disabilities and conduction abnormalities in those patients, albeit transiently (Kaji et al. Ann Neurol 1990 ; 28 ; 582-584). Less

1）我们研究了洋地黄（心脏糖苷）对脱髓鞘神经纤维传导的影响。已证明Digitalis是电源Na/k泵的阻滞剂，可防止轴突膜的超极性，我们的初步证据表明，由于超极性极性导致的高频冲动（速率依赖性阻滞），digitalis克服了未能传递高频冲动（速率依赖性阻滞）。我们的数据还表明，洋地黄会通过降低静息膜电位来部分逆转由于脱髓鞘的完全转换传导块。我们在脱髓鞘的大鼠腹侧根纤维中进行了一项单纤维研究，并在给药digitalis后的脊髓脱髓鞘的大鼠中进行了串行SEP研究，与临床症状相关。2）许多MS患者具有临床上静音的斑块，并且MS的临床恢复通常太快，以至于无法由Remyelelination引起。 MS中的脱髓鞘纤维可传递脉冲，恢复症状后可能是生物学上使用的。 ...更多基于我们先前的研究（Kaji，Suzumura，Sumner，Brain，Brain，Brain，Brain（1988）111; 675-694，附录1），该研究表明，CNS脱髓鞘纤维无法传播高达50 Hz的频率（速率依赖性频率和临床率）的脉冲频率的频率的持续率，以置于跨度的速率，以置于Persist的速度相差，以置于跨度率，以置于Persist opersist的基础，以置于跨度的速度相差。 MS中症状的缓解和继电器：MS中的临床症状可能是由于缺乏完全传导阻滞的速率依赖性阻滞而引起的，因为信息被编码为CNS纤维中使用高频范围（高达250 Hz或更多）的冲动频率（频率调节）。临床恢复是由轴突末端和突触后神经元的自适应过程附加的，导致重新解释改良的脉冲火车。症状复发是通过略微扩展斑块或任何其他因素再次降低了传播的安全系数的原因，进而降低了脱髓鞘纤维可以随之而来的最大频率，从而使在出院模式中所携带的信息不可解释为突触后的神经元所携带的信息。为了测试该假设，我们可以在该模型中构建了一个模型，我们可以在该模型中进行编码，以分析信息的编码，该编码是构成信息的，这些信息是构造的。在脊髓脱髓鞘大鼠的脚垫上振动刺激后的神经元。我们的初步研究表明，由于脱髓鞘的速率依赖性块引起的振动频率的信息丧失（Kaji R，Kimura J等人。提交给大脑）。我们还通过记录脱髓鞘纤维（背柱）和突触后神经元（gracile神经元）以及格拉丝核us的超微结构和HRP研究来阐明恢复过程的机制。我们还研究了该模型中Digitalis对神经编码受损的影响，特别是其逆转率依赖性区块的能力。3）基于上述动物实验，我们检查了静脉二高氧蛋白对临床症状的影响，并诱发了多发性硬化症患者的潜在参数。多氧蛋白是一种数字衍生物，可以成功扭转这些患者的临床疾病和传导异常，尽管瞬时（Kaji等人Ann Neurol 1990; 28; 582-584）。较少的

项目成果

Kaji,R.: "Ouabain reverses conduction dis turbances in single demyelinated nerve fibers" Neurology. 39. 1364-1368 (1989)

Kaji,R.：“哇巴因逆转单个脱髓鞘神经纤维的传导障碍”神经病学。

Kaji R.: "Effect of Digitalis on Clinical Symptoms and Conduction Variables in Patients with Multiple Sclerosis" Ann Neurol. 28. 582-584 (1990)

Kaji R.：“洋地黄对多发性硬化症患者临床症状和传导变量的影响”Ann Neurol。

Kaji R et al.: "Synaptic reorganization after experimental demyelination" Brain Res.

Kaji R 等人：“实验性脱髓鞘后的突触重组”Brain Res。