Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats
Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats
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DOI：
10.1097/01.wcb.0000040400.30600.af
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发表时间：
2003-02-01
影响因子：
6.3
通讯作者：
Schwab, ME
中科院分区：
文献类型：
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作者：
Wiessner, C;Bareyre, FM;Schwab, ME
Nogo-A是一种髓鞘相关的轴突生长抑制蛋白，限制中枢神经系统损伤后的恢复和可塑性。在这项研究中，纯化的抗Nogo-A单抗(7B12)在两个大鼠中风模型上进行了评估，其治疗时间为伤后24小时。在光性血栓性皮质损伤(PCI)和脑室内注射对照小鼠免疫球蛋白G 2周后，长期对侧前爪功能下降到损伤前的55%左右，直到研究的最新时间点(9周)。经皮冠状动脉介入治疗后6~9周，7B12治疗组大鼠前爪功能明显改善，达到病变前水平的70%左右。采用永久性大脑中动脉闭塞(MCAO)的方法建立自发性高血压大鼠(SHR)大脑皮质梗塞模型。对照组在MCAO后4~12周，前爪功能维持在损毁前水平的40%~50%之间。相比之下，7B12治疗组在MCAO后4至7周表现出显著改善，从4周时损伤前水平的约40%到MCAO后7至12周时的约60%至70%。两种模型的治疗都是有效的，而不影响脑梗塞体积或脑萎缩。在脊髓神经解剖学上，7B12治疗组大鼠脊髓中线交叉纤维起源于未损毁的感觉运动皮质明显增多，PCL组为2.3+/-1.5%(对照组：1.1+/-0.5%)，MCAO后为4.5+/-2.2%(对照组：1.8+/-0.8%)。行为结果与颈髓中线交叉纤维的存在显著相关，提示交叉纤维可能参与了经皮冠状动脉介入术后和大脑中动脉阻塞后的前爪功能。结果表明，特异性抗Nogo-A抗体有可能成为一种新的康复治疗方法，具有较长的治疗时间窗。
Nogo-A is a myelin-associated neurite outgrowth inhibitory protein limiting recovery and plasticity after central nervous system injury. In this study, a purified monoclonal anti-Nogo-A antibody (7B12) was evaluated in two rat stroke models with a time-to-treatment of 24 hours after injury. After photothrombotic cortical injury (PCI) and intraventricular infusion of a control mouse immunoglobulin G for 2 weeks, long-term contralateral forepaw function was reduced to about 55% of prelesion performance until the latest time point investigated (9 weeks). Forepaw function was significantly better in the 7B12-treated group 6 to 9 weeks after PCI, and reached about 70% of prelesion levels. Cortical infarcts were also produced in spontaneously hypertensive rats (SHR) by permanent middle cerebral artery occlusion (MCAO). In the control group, forepaw function remained between 40% and 50% of prelesion levels 4 to 12 weeks after MCAO. In contrast, 7B 12-treated groups showed significant improvement between 4 and 7 weeks after MCAO from around 40% of prelesion levels at week 4 to about 60% to 70% at 7 to 12 weeks after MCAO. Treatment in both models was efficacious without influencing infarct volume or brain atrophy. Neuroanatomically in the spinal cord, a significant increase of midline crossing corticospinal fibers originating in the unlesioned sensorimotor cortex was found in 7B12-treated groups, reaching 2.3 +/- 1.5% after PCl (control group: 1.1 +/- 0.5%) and 4.5 +/- 2.2% after MCAO in SHR rats (control group: 1.8 +/- 0.8%). Behavioral outcome and the presence of midline crossing fibers in the cervical spinal cord correlated significantly, suggesting a possible contribution of the crossing fibers for forepaw function after PCI and MCAO. The results suggest that specific anti-Nogo-A antibodies bear potential as a new rehabilitative treatment approach for ischemic stroke with a prolonged time-to-treatment window.