Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats
Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats
复制标题
DOI：
10.1016/j.expneurol.2017.03.012
复制
发表时间：
2017-06-01
影响因子：
5.3
通讯作者：
Ichiyama, Ronaldo M.
中科院分区：
文献类型：
--
作者：
ChenKinon;Marsh, Barnaby C.;Ichiyama, Ronaldo M.
强化训练是不完全性脊髓损伤(SCI)后临床上最成功的治疗方式。随着增强可塑性治疗的出现，了解联合使用时治疗可能如何相互作用变得至关重要。在这里，我们研究了一种合理的方法，将跑步机运动训练与抗体介导的抑制纤维生长抑制蛋白Nogo-A的顺序结合起来。在大而不完全的胸部损伤后，立即用抗Nogo-A抗体或对照抗体治疗(2周)，然后从损伤后3周开始不训练或逐步训练8周。研究发现，顺序联合治疗改善了步态的一致性，减少了脚趾拖拽和攀登错误，就像单独进行训练和抗Nogo-A一样。序贯治疗的动物在两足行走时也采用了更平行的爪子位置，并且比单独治疗的动物表现出更好的总体四足运动恢复。组织学上，序贯疗法诱导最大的皮质脊髓束向尾部发芽进入腰部，并增加了5-羟色胺能突触到腰椎运动神经元的数量。用抗Nogo-A抗体观察到的腰椎运动神经元初级传入发芽和突触形成的增加在训练后减少。序贯治疗的动物也显示出与步行相关的腰椎神经元间活动(c-fos表达)的最高降低。没有观察到对热痛、机械性异位痛觉或病变体积的治疗效果。结果表明，脊髓损伤后及时给予抗Nogo-A抗体并进行高强度的运动训练，可使丧失的运动功能得到较好的恢复，这可能是通过改变脊髓损伤后下行萌发和局部节段性网络之间的相互作用而实现的。(C)2017 Elsevier Inc.保留所有权利。
Intense training is the most clinically successful treatment modality following incomplete spinal cord injuries (SCIs). With the advent of plasticity enhancing treatments, understanding how treatments might interact when delivered in combination becomes critical. Here, we investigated a rational approach to sequentially combine treadmill locomotor training with antibody mediated suppression of the fiber growth inhibitory protein Nogo-A. Following a large but incomplete thoracic lesion, rats were immediately treated with either anti-Nogo-A or control antibody (2 weeks) and then either left untrained or step-trained starting 3 weeks after injury for 8 weeks. It was found that sequentially combined therapy improved step consistency and reduced toe dragging and climbing errors, as seen with training and anti-Nogo-A individually. Animals with sequential therapy also adopted a more parallel paw position during bipedal walking and showed greater overall quadrupedal loco motor recovery than individual treatments. Histologically, sequential therapy induced the greatest corticospinal tract sprouting caudally into the lumbar region and increased the number of serotonergic synapses onto lumbar motoneurons. Increased primary afferent sprouting and synapse formation onto lumbar motoneurons observed with anti-Nogo-A antibody were reduced by training. Animals with sequential therapy also showed the highest reduction of lumbar interneuronal activity associated with walking (c-fos expression). No treatment effects for thermal nociception, mechanical allodynia, or lesion volume were observed. The results demonstrate that sequential administration of anti-Nogo-A antibody followed in time with intensive locomotor training leads to superior recovery of lost locomotor functions, which is probably mediated by changes in the interaction between descending sprouting and local segmental networks after SCI. (C) 2017 Elsevier Inc. All rights reserved.