Department of Neurology, Chiba University School of Medicine, Japan.
Curr Mol Pharmacol. 2008 Jan;1(1):61-7. doi: 10.2174/1874467210801010061.
Axonal excitability testing can provide new insights into the ionic mechanisms underlying the pathophysiology of hyperexcitability of motor and sensory axons in human neuropathies. Threshold tracking was developed in the 1990's to non-invasively measure a number of axonal excitability indices that depend on sodium and potassium channel function, and this makes it possible to monitor the effects of pharmacologic intervention with ion channel modulators. This paper reviews recent advances in ionic-pathophysiological studies in humans. (1) Neuropathic pain or muscle cramp/fasciculation is partly caused by hyperexcitability of the injured axons. The enhanced excitability can result from altered ion channel function; such as an increase in persistent sodium currents. Persistent sodium currents can be reliably estimated using threshold tracking. In peripheral neuropathy, persistent sodium currents usually increase possibly due to over-expression of sodium channels associated with axonal regeneration, and could be responsible for ectopic firings. Administration of sodium channel blockers such as mexiletine, results in marked alleviation of muscle cramping in parallel with a decrease in nodal persistent sodium currents. (2) In diabetic neuropathy, the activation of the polyol pathway mediated by an enzyme, aldose reductase, leads to reduced Na(+)/K(+) pump activity, and intra-axonal sodium accumulation; sodium currents are reduced presumably due to decreased trans-axonal sodium gradient. Aldose reductase inhibitiors improve nodal sodium currents, as well as nerve conduction, and this can be objectively assessed by threshold tracking. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms by monitoring the corresponding ionic currents. is of clinical relevance, because once a specific ionic conductance is identified, pharmacologic blocking or modulation could provide a new therapeutic option.
轴突兴奋性测试可以为运动和感觉轴突在人类神经病变中的过度兴奋性的离子机制提供新的见解。阈值追踪技术于 20 世纪 90 年代开发，用于非侵入性地测量依赖于钠和钾通道功能的许多轴突兴奋性指数，这使得监测离子通道调节剂的药理干预效果成为可能。本文综述了人类离子病理生理学研究的最新进展。（1）神经病理性疼痛或肌肉痉挛/抽搐部分是由损伤轴突的过度兴奋性引起的。兴奋性的增强可能是由于离子通道功能的改变；例如，持续钠电流的增加。使用阈值追踪可以可靠地估计持续钠电流。在周围神经病变中，持续钠电流通常会增加，可能是由于与轴突再生相关的钠通道过度表达，并且可能负责异位放电。钠离子通道阻滞剂（如美西律）的给药导致肌肉痉挛明显缓解，同时节点持续钠电流减少。（2）在糖尿病神经病变中，由醛糖还原酶介导的多元醇途径的激活导致 Na(+)/K(+)泵活性降低，轴内钠离子积累；钠离子电流减少可能是由于跨轴钠离子梯度降低所致。醛糖还原酶抑制剂可改善节点钠电流和神经传导，这可以通过阈值追踪进行客观评估。对人类受试者的离子通道病理生理学的研究最近才开始。通过监测相应的离子电流来研究离子机制具有临床相关性，因为一旦确定了特定的离子电导，药物阻断或调节就可以提供新的治疗选择。
