A Mouse Model of Bilateral Cervical Contusion-Compression Spinal Cord Injury
A Mouse Model of Bilateral Cervical Contusion-Compression Spinal Cord Injury
复制标题
DOI：
10.1089/neu.2016.4708
复制
发表时间：
2017-03-01
影响因子：
4.2
通讯作者：
Fehlings, Michael G.
中科院分区：
文献类型：
--
作者：
Forgione, Nicole;Chamankhah, Mahmood;Fehlings, Michael G.
在所有创伤性脊髓损伤（SCI）病例中，超过一半的病例发生颈脊髓损伤（cSCI），但我们缺乏可以在这些患者中产生显著功能恢复的治疗方法。cSCI动物模型的发展将有助于临床前评估治疗和了解基本的病理生理机制。在这里，我们描述了一个临床相关的模型，颈部挫伤压缩损伤的小鼠。使用改良的动脉瘤夹，我们产生了一个双侧的，不完全的损伤，模仿最常见的人类挫伤压缩损伤。我们在术后8周跟踪受伤和假手术（仅椎板切除术）动物的恢复情况。行为测试，包括Basso小鼠量表（BMS），钢丝悬挂，握力和CatWalk自动步态分析，表明虽然自然恢复是有限的，但它发生在损伤的亚急性期（SCI后7-14天）的临床相关窗口。BMS评分表明，虽然受伤的动物可以走动，但它们不能恢复正常的运动能力。CatWalk分析定量显示协调和运动能力丧失，恢复最小。钢丝悬挂和握力测试证实受伤动物的前肢运动强度显著下降。在亚急性期（7天时间点）和慢性期（8周时间点）进行的组织学分析表明，损伤中心在SCI后7天形成。蛋白激酶C γ（PKC γ）染色轴突的体积分析显示，这种损伤导致损伤部位尾侧皮质脊髓束的显著损伤。最后，我们使用定量实时聚合酶链反应来显示与炎症和神经胶质瘢痕形成相关的基因由于损伤而上调。这项研究证实，我们可以有效地在小鼠中建立双侧颈椎损伤模型，并为未来使用该模型评估治疗方法的研究提供了框架。
Cervical spinal cord injury (cSCI) occurs in over half of all cases of traumatic spinal cord injury (SCI), yet we lack therapies that can generate significant functional recovery in these patients. The development of animal models of cSCI will aid in the pre-clinical assessment of therapies and in understanding basic pathophysiological mechanisms. Here, we describe a clinically relevant model of cervical contusion-compression injury in the mouse. Using a modified aneurysm clip, we generated a bilateral, incomplete injury that mimics contusion-compression injuries most commonly observed in humans. We followed the recovery of injured and sham-operated (laminectomy-only) animals for 8 weeks post-surgery. Behavioral tests, including the Basso Mouse Scale (BMS), wire hanging, grip strength, and CatWalk automated gait analysis, showed that while natural recovery is limited, it occurs in a clinically relevant window during the subacute phase of injury (7-14 days post-SCI). BMS scoring demonstrated that, while injured animals are ambulatory, they do not recover normal locomotor ability. CatWalk analysis quantitatively showed a loss of coordination and motor ability, with minimal recovery. The wire hanging and grip strength tests confirmed a significant decrease in forelimb motor strength in injured animals. Histological analysis carried out during the subacute phase (7-day time point) and chronic phase (8-week time point) demonstrated that the lesion epicenter is formed by 7 days post-SCI. Volumetric analysis of protein kinase C gamma (PKCgamma)-stained axons revealed that this injury results in significant damage to the corticospinal tract caudal to the injury site. Finally, we used quantitative real-time polymerase chain reaction to show that genes associated with inflammation and glial scarring are upregulated as a result of injury. This study confirms that we can effectively model bilateral cervical injury in the mouse and provides a framework for future studies using this model to assess therapies.