School of Medicine and Dentistry, University of Rochester, Rochester, New York.
Department of Orthopaedic Surgery, University of California at Irvine, Irvine, California.
J Bone Joint Surg Am. 2019 Mar 20;101(6):523-530. doi: 10.2106/JBJS.18.00162.
Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin (EPO), as treatments for surgically induced ischemia and as adjuvants to surgical decompression.
Peripheral nerve compression was induced in wild-type mice by placing an inert silicone sleeve around the sciatic nerve. Decompression surgery was performed at 6 weeks with mice receiving 4-AP, EPO, or saline solution either during and after compression or only after decompression. A nerve conduction study and morphometric analyses were performed to compare the extent of the injury and the efficacy of the therapies, and the findings were subjected to statistical analysis.
During peripheral nerve compression, there was a progressive decline in nerve conduction velocity compared with that in sham-treatment animals, in which nerve conduction velocity remained normal (∼55 m/s). Mice treated with 4-AP or EPO during the compression phase had significantly smaller declines in nerve conduction velocity and increased plateau nerve conduction velocities compared with untreated controls (animals that received saline solution). Histomorphometric analyses of newly decompressed nerves (i.e., nerves that underwent decompression on the day that the mouse was sacrificed) revealed that both treated groups had significantly greater proportions of large (>5-µm) axons than the untreated controls. Following surgical decompression, all animals recovered to a normal baseline nerve conduction velocity by day 15; however, treatment significantly accelerated improvement (in both the 4-AP and the EPO group), even when it was only started after decompression. Histomorphometric analyses at 7 and 15 days following surgical decompression revealed significantly increased myelin thickness and significantly greater proportions of large axons among the treated animals.
Both the 4-AP and the EPO-treated group demonstrated improvements in tissue architectural and electrodiagnostic measurements, both during and after peripheral nerve compression, compared with untreated mice.
Peripheral nerve decompression is one of the most commonly performed procedures in orthopaedic surgery. We believe that there is reason for some optimism about the translation of our findings to the clinical setting. Our findings in this murine model suggest that 4-AP and EPO may lessen the effects of nerve entrapment and that the use of these agents after decompression may speed and perhaps otherwise optimize recovery after surgery.
周围神经压迫和嵌顿会使人虚弱。我们使用一种经过验证的周围神经压迫动物模型，研究了两种已批准用于人类其他用途的药物——4-氨基吡啶（4-AP）和促红细胞生成素（EPO）——作为手术诱导缺血的治疗方法，以及作为手术减压的辅助手段。
通过在坐骨神经周围放置惰性硅酮套管，在野生型小鼠中诱导周围神经压迫。在 6 周时进行减压手术，接受 4-AP、EPO 或生理盐水治疗的小鼠在压迫期间和压迫后或仅在减压后接受治疗。进行神经传导研究和形态计量学分析，以比较损伤程度和治疗效果，并对结果进行统计学分析。
在周围神经压迫期间，与假手术治疗动物（神经传导速度保持正常，约 55 m/s）相比，神经传导速度逐渐下降。在压迫阶段接受 4-AP 或 EPO 治疗的小鼠，与未治疗对照组（接受生理盐水的动物）相比，神经传导速度下降幅度较小，平台神经传导速度增加。对新减压神经（即在处死小鼠当天进行减压的神经）进行形态计量学分析显示，与未治疗对照组相比，两组治疗组的大（>5-µm）轴突比例均显著增加。手术后，所有动物在第 15 天恢复到正常的基础神经传导速度；然而，即使仅在减压后开始治疗，治疗也显著加速了恢复。手术后 7 天和 15 天的形态计量学分析显示，在治疗组中，髓鞘厚度明显增加，大轴突比例明显增加。
与未治疗的小鼠相比，在周围神经压迫期间和之后，4-AP 和 EPO 治疗组的组织结构和电诊断测量均有改善。
周围神经减压是矫形外科最常进行的手术之一。我们相信，我们在这种鼠模型中的发现有可能转化为临床应用，这是有一定理由持乐观态度的。我们在该鼠模型中的发现表明，4-AP 和 EPO 可能减轻神经嵌顿的影响，并且在减压后使用这些药物可能会加速并可能优化手术后的恢复。
