Delayed Anti-Nogo-A Antibody Application after Spinal Cord Injury Shows Progressive Loss of Responsiveness
Delayed Anti-Nogo-A Antibody Application after Spinal Cord Injury Shows Progressive Loss of Responsiveness
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DOI：
10.1089/neu.2011.1752
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发表时间：
2012-02-01
影响因子：
4.2
通讯作者：
Schwab, Martin E.
中科院分区：
文献类型：
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作者：
Gonzenbach, Roman R.;Zoerner, Bjoern;Schwab, Martin E.
阻断髓鞘蛋白Nogo-A或其信号通路的功能是克服成人中枢神经系统（CNS）重要的神经突生长抑制因子，增强脑或脊髓损伤后轴突再生和可塑性的一种很有希望的方法。几项研究表明，在成年啮齿动物中，抗nogo - a抗体、nogo受体拮抗剂或抑制下游介质RhoA/ROCK治疗后，轴突再生和代偿性发芽增加，功能恢复明显改善。用抗nogo - a抗体对脊髓损伤的猕猴进行的概念验证研究重复了这些发现；最近，脊髓损伤患者的临床试验已经开始。然而，成功的Nogo-A功能阻断治疗的最佳时间窗尚未确定。我们研究了急性以及1或2周延迟鞘内注射抗nogo - a抗体对成年大鼠大面积解剖不完整胸脊髓损伤后皮质脊髓束（CST）轴突再生和运动功能恢复的影响。我们发现受损的CST纤维在急性或延迟1周治疗后再生超过几毫米，但在延迟2周开始抗体治疗时则没有。急性或延迟1周抗nogo - a抗体治疗的大鼠游泳和窄梁穿越恢复良好，但延迟2周组则没有。这些结果表明，在成年啮齿动物中，抗nogo - a抗体治疗脊髓病变的时间限制在2周以内。
Blocking the function of the myelin protein Nogo-A or its signaling pathway is a promising method to overcome an important neurite growth inhibitory factor of the adult central nervous system (CNS), and to enhance axonal regeneration and plasticity after brain or spinal cord injuries. Several studies have shown increased axonal regeneration and enhanced compensatory sprouting, along with substantially improved functional recovery after treatment with anti-Nogo-A antibodies, Nogo-receptor antagonists, or inhibition of the downstream mediator RhoA/ROCK in adult rodents. Proof-of-concept studies in spinal cord-injured macaque monkeys with anti-Nogo-A antibodies have replicated these findings; recently, clinical trials in spinal cord-injured patients have begun. However, the optimal time window for successful Nogo-A function blocking treatments has not yet been determined. We studied the effect of acute as well as 1- or 2-weeks delayed intrathecal anti-Nogo-A antibody infusions on the regeneration of corticospinal tract (CST) axons and the recovery of motor function after large but anatomically incomplete thoracic spinal cord injuries in adult rats. We found that lesioned CST fibers regenerated over several millimeters after acute or 1-week-delayed treatments, but not when the antibody treatment was started with a delay of 2weeks. Swimming and narrow beam crossing recoveredwell in rats treated acutely or with a 1-week delay with anti-Nogo-A antibodies, but not in the 2-week-delayed group. These results show that the time frame for treatment of spinal cord lesions with anti-Nogo-A antibodies is restricted to less than 2 weeks in adult rodents.