Delayed Applications of L1 and Chondroitinase ABC Promote Recovery after Spinal Cord Injury
Delayed Applications of L1 and Chondroitinase ABC Promote Recovery after Spinal Cord Injury
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DOI：
10.1089/neu.2011.2290
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Schachner, Melitta
中科院分区：
文献类型：
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作者：
Lee, Hyun Joon;Bian, Shan;Schachner, Melitta
损伤脊髓的抑制环境是成年哺乳动物功能恢复和轴突再生的障碍。我们之前已经证明，在成年小鼠急性胸压迫损伤时注射编码L1细胞粘附分子（AAV-L1）的腺相关病毒（AAV-L1）促进运动恢复，这与改善星形胶质细胞增生和改善腰椎轴突再生有关。在本研究中，我们研究了在小鼠脊髓损伤后3周延迟注射AAV-L1、软骨素酶ABC (Chase)，或两种药物联合注射是否也会促进恢复。Basso小鼠量表显示，与注射AAV编码绿色荧光蛋白（AAV- gfp）的对照组相比，各治疗组在用药12周后运动恢复增强。然而，通过单帧运动分析对后肢功能的调查显示，L1过表达而不是注射Chase，改善了没有体重支持的自主运动，而注射Chase，而不是L1过表达，增强了行走时的体重支持。联合应用AAV-L1和Chase的小鼠在这两个参数上都有改善。联合应用后增强的运动恢复与损伤后15周运动神经元细胞体的胆碱能和gaba能末端以及层特异性谷氨酸能感觉传入的密度增加相关，表明损伤部位下方的腰椎脊髓突触重排增强。这些发现提示L1过表达联合Chase应用可能有助于亚慢性脊髓损伤的治疗。
The inhibitory environment of the injured spinal cord is an obstacle to functional recovery and axonal regeneration in adult mammals. We had previously shown that injection of adeno-associated virus (AAV) encoding the L1 cell adhesion molecule (AAV-L1) at the time of acute thoracic compression injury of adult mice promotes locomotor recovery, which is associated with ameliorated astrogliosis and improved axonal regeneration in the lumbar spinal cord. In the present study, we investigated whether delayed injection of AAV-L1, chondroitinase ABC (Chase), or the combination of the two agents into the mouse spinal cord 3 weeks after injury would also lead to improved recovery. The Basso Mouse Scale showed enhanced locomotor recovery 12 weeks after application of the agents in all treatment groups compared to the control group that was injected with AAV encoding green fluorescent protein (AAV-GFP). Investigation of hindlimb function using single-frame motion analysis revealed, however, that L1 overexpression, but not injection of Chase, improved voluntary movements without body weight support, whereas injection of Chase, but not L1 overexpression, enhanced body weight support during stepping. Mice with the combined application of AAV-L1 and Chase showed improvement in both parameters. Enhanced motor recovery after combined application correlated with increased densities of cholinergic and GABAergic terminals at motoneuronal cell bodies, and of lamina-specific glutamatergic sensory afferents 15 weeks after injury, indicating enhanced synaptic rearrangements in the lumbar spinal cord below the lesion site. These findings suggest that L1 overexpression combined with Chase application may contribute to the treatment of sub-chronic spinal cord injury.