Gold B G, Katoh K, Storm-Dickerson T
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201-3098, USA.
J Neurosci. 1995 Nov;15(11):7509-16. doi: 10.1523/JNEUROSCI.15-11-07509.1995.
The axonal regenerative properties of the new immunosuppressant drug FK506 (tacrolimus) are further explored in this continuing study. In an initial report (Gold et al., 1994a), we described the ability of FK506 to reduce the time until return of function in the hind feet of rats following a sciatic nerve crush. In the present study, we examined the morphological correlate underlying this enhancement of functional recovery. In rats receiving daily subcutaneous injections of FK506 (1.0 mg/kg) for 18 d following a sciatic nerve crush the regenerating axons appeared larger in size compared to saline-injected control animals. Morphometric analysis of axonal calibers in the soleus nerve demonstrated that mean axonal areas for the largest 30% of axons were increased over axotomized control values by 93% in the FK506-treated animals. Next, the rate of axonal regeneration was determined by radiolabeling the L5 dorsal root ganglion (DRG) at 9 and 14 d following axotomy. Regression analysis of the outgrowth distances for sensory axons between 10 and 15 d revealed a 16% increase in regeneration rate. Electron microscopy of intramuscular nerve branches in the interosseus muscles confirmed that the axons in the FK506-treated animals were further advanced toward their targets; in some instances, axons were shown to reinnervate muscle spindles. The results are discussed in terms of the known ability of FK506 to inhibit the activity protein phosphatase 2B (calcineurin).
在这项持续研究中，我们进一步探究了新型免疫抑制剂FK506（他克莫司）的轴突再生特性。在最初的一份报告中（Gold等人，1994a），我们描述了FK506能够缩短大鼠坐骨神经挤压伤后后肢功能恢复的时间。在本研究中，我们检查了这种功能恢复增强背后的形态学关联。在坐骨神经挤压伤后，对大鼠进行为期18天的每日皮下注射FK506（1.0毫克/千克），与注射生理盐水的对照动物相比，再生轴突看起来更大。对比目鱼肌神经轴突直径的形态计量分析表明，在接受FK506治疗的动物中，最大30%轴突的平均轴突面积比轴突切断后的对照值增加了93%。接下来，通过在轴突切断后第9天和第14天对L5背根神经节（DRG）进行放射性标记来确定轴突再生的速率。对10至15天之间感觉轴突生长距离的回归分析显示再生速率提高了16%。对骨间肌内肌神经分支的电子显微镜检查证实，接受FK506治疗的动物中的轴突向其靶标进一步生长；在某些情况下，轴突显示重新支配肌梭。我们根据FK506抑制活性蛋白磷酸酶2B（钙调神经磷酸酶）的已知能力对结果进行了讨论。
