Treatment With the Neutralizing Antibody Against Repulsive Guidance Molecule-a Promotes Recovery From Impaired Manual Dexterity in a Primate Model of Spinal Cord Injury
Treatment With the Neutralizing Antibody Against Repulsive Guidance Molecule-a Promotes Recovery From Impaired Manual Dexterity in a Primate Model of Spinal Cord Injury
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DOI：
10.1093/cercor/bhx338
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发表时间：
2019-02-01
期刊：
影响因子：
3.7
通讯作者：
Takada, Masahiko
中科院分区：
文献类型：
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作者：
Nakagawa, Hiroshi;Ninomiya, Taihei;Takada, Masahiko
成熟哺乳动物中枢神经系统中的轴突在损伤后仅具有有限的生长/再生能力，并且因此在脊髓损伤（SCI）中运动功能的自发恢复不是很有希望。为了促进SCI后的功能恢复，关键是皮质脊髓束（CST）纤维通过增强轴突生长/再生与靶脊髓神经元正确地重新连接。在这里，我们应用抗体治疗排斥导向分子-a（RGMa）的SCI猴模型。我们发现，在颈髓损伤部位周围的上调RGMa的抑制导致恢复受损的手动灵巧性，通过加重穿透CST纤维到椎板VII和IX，脊髓中间神经元和运动神经元分别位于。此外，皮质内微刺激后的药理学失活显示，在我们的SCI模型的后期阶段，对侧病灶，而不是同侧病灶，初级运动皮质在功能恢复中起着至关重要的作用。目前的数据表明，SCI后用针对RGMa的中和抗体治疗是在灵长类动物中实现恢复的手灵巧性的潜在靶标。
Axons in the mature mammalian central nervous system have only a limited capacity to grow/regenerate after injury, and spontaneous recovery of motor functions is therefore not greatly expected in spinal cord injury (SCI). To promote functional recovery after SCI, it is critical that corticospinal tract (CST) fibers reconnect properly with target spinal neurons through enhanced axonal growth/regeneration. Here, we applied antibody treatment against repulsive guidance molecule-a (RGMa) to a monkey model of SCI. We found that inhibition of upregulated RGMa around the lesioned site in the cervical cord resulted in recovery from impaired manual dexterity by accentuated penetration of CST fibers into laminae VII and IX, where spinal interneurons and motoneurons are located, respectively. Furthermore, pharmacological inactivation following intracortical microstimulation revealed that the contralesional, but not the ipsilesional, primary motor cortex was crucially involved in functional recovery at a late stage in our SCI model. The present data indicate that treatment with the neutralizing antibody against RGMa after SCI is a potential target for achieving restored manual dexterity in primates.