Thompson Hilaire J, Marklund Niklas, LeBold David G, Morales Diego M, Keck Carrie A, Vinson Mary, Royo Nicolas C, Grundy Robert, McIntosh Tracy K
Traumatic Brain Injury Laboratory, Department of Neurosurgery, The University of Pennsylvania, Philadelphia, PA, USA, and Department of Neurosurgery, Uppsala University Hospital, Sweden.
Eur J Neurosci. 2006 Dec;24(11):3063-72. doi: 10.1111/j.1460-9568.2006.05197.x.
Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n=102) were subjected to either lateral fluid percussion brain injury (n=59) or sham injury (n=43). In surviving animals, beginning at 1 h post-injury, 8.64 microg anti-MAG mAb (n=33 injured, n=21 sham) or control IgG (n=26 injured, n=22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n=14 sham, n=11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P<0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P<0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.
轴突损伤是创伤性脑损伤（TBI）的一个标志，并且与不良的临床结果相关。中枢神经系统损伤后，轴突再生能力很差，部分原因是存在与髓磷脂相关的抑制轴突生长的分子，包括髓磷脂相关糖蛋白（MAG）。MAG在实验性TBI后的神经行为缺陷和组织损失中的作用仍未得到探索，在本研究中使用一种MAG特异性单克隆抗体（mAb）对其进行了评估。将麻醉的大鼠（n = 102）分为两组，分别进行侧方液压冲击脑损伤（n = 59）或假手术（n = 43）。在存活的动物中，从损伤后1小时开始，向脑室内注入8.64微克抗MAG mAb（损伤组n = 33，假手术组n = 21）或对照IgG（损伤组n = 26，假手术组n = 22），持续72小时。其中一组大鼠（假手术组n = 14，损伤组n = 11）在损伤后72小时处死，用于验证药物扩散和MAG免疫组织化学。所有其他动物在损伤后长达8周的时间内，使用神经运动、感觉和认知功能测试进行评估。在损伤后8周时，还评估了半球组织损失情况。在损伤后72小时，脑损伤动物同侧皮质、丘脑和海马中MAG的免疫反应性增加，并且在海马、海马伞和脑室中可检测到抗MAG mAb。与脑损伤后接受IgG治疗的动物相比，接受抗MAG mAb治疗的脑损伤动物在损伤后6周和8周时感觉运动功能的恢复明显改善（P < 0.01）。此外，在损伤后8周时，与脑损伤对照组相比，接受抗MAG mAb治疗的脑损伤动物的认知功能明显改善，半球组织损失减少（P < 0.05）。这些结果表明，MAG可能参与了实验性TBI的病理生理过程，针对MAG的治疗策略可能适合进一步评估。
