Lenzlinger P M, Shimizu S, Marklund N, Thompson H J, Schwab M E, Saatman K E, Hoover R C, Bareyre F M, Motta M, Luginbuhl A, Pape R, Clouse A K, Morganti-Kossmann C, McIntosh T K
Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA.
Neuroscience. 2005;134(3):1047-56. doi: 10.1016/j.neuroscience.2005.04.048.
Traumatic brain injury causes long-term neurological motor and cognitive deficits, often with limited recovery. The inability of CNS axons to regenerate following traumatic brain injury may be due, in part, to inhibitory molecules associated with myelin. One of these myelin-associated proteins, Nogo-A, inhibits neurite outgrowth in vitro, and inhibition of Nogo-A in vivo enhances axonal outgrowth and sprouting and improves outcome following experimental CNS insults. However, the involvement of Nogo-A in the neurobehavioral deficits observed in experimental traumatic brain injury remains unknown and was evaluated in the present study using the 11C7 monoclonal antibody against Nogo-A. Anesthetized, male Sprague-Dawley rats were subjected to either lateral fluid percussion brain injury of moderate severity (2.5-2.6 atm) or sham injury. Beginning 24 h post-injury, monoclonal antibody 11C7 (n=17 injured, n=6 shams included) or control Ab (IgG) (n=16 injured, n=5 shams included) was infused at a rate of 5 microl/h over 14 days into the ipsilateral ventricle using osmotic minipumps connected to an implanted cannula. Rats were assessed up to 4 weeks post-injury using tests for neurological motor function (composite neuroscore, and sensorimotor test of adhesive paper removal) and, at 4 weeks, cognition was assessed using the Morris water maze. Hippocampal CA3 pyramidal neuron damage and corticospinal tract sprouting, using an anterograde tracer (biotinylated dextran amine), were also evaluated. Brain injury significantly increased sprouting from the uninjured corticospinal tract but treatment with monoclonal antibody 11C7 did not further increase the extent of sprouting nor did it alter the extent of CA3 cell damage. Animals treated with 11C7 showed no improvement in neurologic motor deficits but did show significantly improved cognitive function at 4 weeks post-injury when compared with brain-injured, IgG-treated animals. To our knowledge, the present findings are the first to suggest that (1) traumatic brain injury induces axonal sprouting in the corticospinal tract and this sprouting may be independent of myelin-associated inhibitory factors and (2) that post-traumatic inhibition of Nogo-A may promote cognitive recovery unrelated to sprouting in the corticospinal tract or neuroprotective effects on hippocampal cell loss following experimental traumatic brain injury.
创伤性脑损伤会导致长期的神经运动和认知缺陷，恢复往往有限。创伤性脑损伤后中枢神经系统轴突无法再生，部分原因可能是与髓磷脂相关的抑制分子。这些髓磷脂相关蛋白之一，Nogo-A，在体外抑制神经突生长，在体内抑制Nogo-A可增强轴突生长和发芽，并改善实验性中枢神经系统损伤后的结果。然而，Nogo-A在实验性创伤性脑损伤中观察到的神经行为缺陷中的作用尚不清楚，本研究使用针对Nogo-A的11C7单克隆抗体对其进行了评估。将麻醉的雄性Sprague-Dawley大鼠进行中度严重程度（2.5-2.6个大气压）的侧方液体冲击脑损伤或假手术。损伤后24小时开始，使用连接到植入套管的渗透微型泵，以5微升/小时的速度在14天内将单克隆抗体11C7（n=17只损伤大鼠，n=6只假手术大鼠）或对照抗体（IgG）（n=16只损伤大鼠，n=5只假手术大鼠）注入同侧脑室。使用神经运动功能测试（综合神经评分和去除粘纸的感觉运动测试）对大鼠进行损伤后长达4周的评估，并在4周时使用莫里斯水迷宫评估认知。还使用顺行示踪剂（生物素化葡聚糖胺）评估海马CA3锥体神经元损伤和皮质脊髓束发芽。脑损伤显著增加了未损伤皮质脊髓束的发芽，但用单克隆抗体11C7治疗并未进一步增加发芽程度，也未改变CA3细胞损伤程度。与脑损伤的IgG治疗动物相比，用11C7治疗的动物在神经运动缺陷方面没有改善，但在损伤后4周时认知功能有显著改善。据我们所知，本研究结果首次表明：（1）创伤性脑损伤可诱导皮质脊髓束轴突发芽，且这种发芽可能与髓磷脂相关抑制因子无关；（2）创伤后抑制Nogo-A可能促进认知恢复，这与皮质脊髓束发芽或对实验性创伤性脑损伤后海马细胞丢失的神经保护作用无关。
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