Moldovan Mihai, Alvarez Susana, Rosberg Mette R, Krarup Christian
Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Neurophysiology, NF3063, Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen, Denmark.
Eur J Neurosci. 2016 Feb;43(3):388-403. doi: 10.1111/ejn.13047. Epub 2015 Oct 5.
Excitability of regenerated fibers remains impaired due to changes in both passive cable properties and alterations in the voltage-dependent membrane function. These abnormalities were studied by mathematical modeling in human regenerated nerves and experimental studies in mice. In three adult male patients with surgically repaired complete injuries of peripheral nerves of the arm 22 months-26 years prior to investigation, deviation of excitability measures was explained by a hyperpolarizing shift in the resting membrane potential and an increase in the passive 'Barrett and Barrett' conductance (GBB) bridging the nodal and internodal compartments. These changes were associated with an increase in the 'fast' K(+) conductance and the inward rectifier conductance (GH). Similar changes were found in regenerated mouse tibial motor axons at 1 month after a sciatic crush lesion. During the first 5 months of regeneration, GH showed partial recovery, which paralleled that in GBB. The internodal length remained one-third of normal. Excitability abnormalities could be reversed by the energy-dependent Na(+)/K(+) pump blocker ouabain resulting in membrane depolarization. Stressing the Na(+) pumping system during a strenuous activity protocol triggered partial Wallerian degeneration in regenerated nerves but not in control nerves from age-matched mice. The current data suggest that the nodal voltage-gated ion channel machinery is restored in regenerated axons, although the electrical separation from the internodal compartment remains compromised. Due to the persistent increase in number of nodes, the increased activity-dependent Na(+) influx could lead to hyperactivity of the Na(+)/K(+) pump resulting in membrane hyperpolarization and neurotoxic energy insufficiency during strenuous activity.
由于被动电缆特性的变化以及电压依赖性膜功能的改变，再生纤维的兴奋性仍然受损。这些异常通过对人类再生神经的数学建模和对小鼠的实验研究进行了探讨。在三名成年男性患者中，他们的手臂周围神经在手术修复后完全损伤，时间为调查前22个月至26年，兴奋性测量的偏差可由静息膜电位的超极化偏移以及连接结间和结间区室的被动“巴雷特和巴雷特”电导（GBB）增加来解释。这些变化与“快速”钾离子电导和内向整流电导（GH）的增加有关。在坐骨神经挤压损伤后1个月的再生小鼠胫神经运动轴突中也发现了类似的变化。在再生的前5个月中，GH显示出部分恢复，这与GBB的恢复情况相似。结间长度仍为正常的三分之一。能量依赖性钠钾泵阻滞剂哇巴因可使兴奋性异常逆转，导致膜去极化。在剧烈活动方案中对钠泵系统施加压力会引发再生神经中的部分华勒氏变性，但在年龄匹配小鼠的对照神经中则不会。目前的数据表明，尽管与结间区室的电隔离仍然受损，但再生轴突中的结电压门控离子通道机制已恢复。由于结数量持续增加，活动依赖性钠内流增加可能导致钠钾泵过度活跃，从而在剧烈活动期间导致膜超极化和神经毒性能量不足。
