Brain Research Institute, University and ETH of Zurich, Zurich, Switzerland.
Eur J Neurosci. 2011 Oct;34(8):1256-67. doi: 10.1111/j.1460-9568.2011.07862.x. Epub 2011 Oct 13.
To encourage re-establishment of functional innervation of ipsilateral lumbar motoneurons by descending fibers after an intervening lateral thoracic (T10) hemisection (Hx), we treated adult rats with the following agents: (i) anti-Nogo-A antibodies to neutralize the growth-inhibitor Nogo-A; (ii) neurotrophin-3 (NT-3) via engineered fibroblasts to promote neuron survival and plasticity; and (iii) the NMDA-receptor 2d (NR2d) subunit via an HSV-1 amplicon vector to elevate NMDA receptor function by reversing the Mg(2+) block, thereby enhancing synaptic plasticity and promoting the effects of NT-3. Synaptic responses evoked by stimulation of the ventrolateral funiculus ipsilateral and rostral to the Hx were recorded intracellularly from ipsilateral lumbar motoneurons. In uninjured adult rats short-latency (1.7-ms) monosynaptic responses were observed. After Hx these monosynaptic responses were abolished. In the Nogo-Ab + NT-3 + NR2d group, long-latency (approximately 10 ms), probably polysynaptic, responses were recorded and these were not abolished by re-transection of the spinal cord through the Hx area. This suggests that these novel responses resulted from new connections established around the Hx. Anterograde anatomical tracing from the cervical grey matter ipsilateral to the Hx revealed increased numbers of axons re-crossing the midline below the lesion in the Nogo-Ab + NT-3 + NR2d group. The combined treatment resulted in slightly better motor function in the absence of adverse effects (e.g. pain). Together, these results suggest that the combination treatment with Nogo-Ab + NT-3 + NR2d can produce a functional 'detour' around the lesion in a laterally hemisected spinal cord. This novel combination treatment may help to improve function of the damaged spinal cord.
为了鼓励在中间的外侧胸部 (T10) 横断 (Hx) 后，通过下行纤维重建同侧腰运动神经元的功能神经支配，我们用以下药物治疗成年大鼠：（i）抗 Nogo-A 抗体中和生长抑制剂 Nogo-A；（ii）通过工程化成纤维细胞的神经营养因子 3（NT-3）促进神经元存活和可塑性；和（iii）通过 HSV-1 扩增子载体的 NMDA 受体 2d（NR2d）亚基，通过逆转 Mg(2+) 阻断来提高 NMDA 受体功能，从而增强突触可塑性并促进 NT-3 的作用。通过刺激 Hx 同侧和前方腹外侧束记录同侧腰运动神经元的细胞内记录。在未受伤的成年大鼠中，观察到短潜伏期（1.7-ms）单突触反应。在 Hx 之后，这些单突触反应被消除了。在 Nogo-Ab + NT-3 + NR2d 组中，记录到长潜伏期（约 10 ms），可能是多突触反应，并且通过重新横切脊髓穿过 Hx 区域，这些反应没有被消除。这表明这些新的反应是由于在 Hx 周围建立的新连接。从 Hx 同侧颈灰质的顺行解剖示踪显示，在 Nogo-Ab + NT-3 + NR2d 组中，在损伤下方中线重新交叉的轴突数量增加。联合治疗在没有不良反应（例如疼痛）的情况下导致运动功能略有改善。总之，这些结果表明，Nogo-Ab + NT-3 + NR2d 的联合治疗可以在横向横断脊髓中产生功能“绕道”。这种新的联合治疗可能有助于改善受损脊髓的功能。
