Dobkin Bruce H
Department of Neurology, Reed Neurologic Research Center, University of California Los Angeles, Los Angeles, California 90095, USA.
Dev Neurobiol. 2007 Aug;67(9):1133-47. doi: 10.1002/dneu.20514.
Clinicians who seek interventions for neural repair in patients with paralysis and other impairments may extrapolate the results of cell culture and rodent experiments into the framework of a preclinical study. These experiments, however, must be interpreted within the context of the model and the highly constrained hypothesis and manipulation being tested. Rodent models of repair for stroke and spinal cord injury offer examples of potential pitfalls in the interpretation of results from developmental gene activation, transgenic mice, endogeneous neurogenesis, cellular transplantation, axon regeneration and remyelination, dendritic proliferation, activity-dependent adaptations, skills learning, and behavioral testing. Preclinical experiments that inform the design of human trials ideally include a lesion of etiology, volume and location that reflects the human disease; examine changes induced by injury and by repair procedures both near and remote from the lesion; distinguish between reactive molecular and histologic changes versus changes critical to repair cascades; employ explicit training paradigms for the reacquisition of testable skills; correlate morphologic and physiologic measures of repair with behavioral measures of task reacquisition; reproduce key results in more than one laboratory, in different strains or species of rodent, and in a larger mammal; and generalize the results across several disease models, such as axonal regeneration in a stroke and spinal cord injury platform. Collaborations between basic and clinical scientists in the development of translational animal models of injury and repair can propel experiments for ethical bench-to-bedside therapies to augment the rehabilitation of disabled patients.
寻求为瘫痪及其他损伤患者进行神经修复干预的临床医生，可能会将细胞培养和啮齿动物实验的结果外推到临床前研究的框架中。然而，这些实验必须在模型以及所测试的高度受限的假设和操作的背景下进行解释。中风和脊髓损伤修复的啮齿动物模型为发育基因激活、转基因小鼠、内源性神经发生、细胞移植、轴突再生和髓鞘再生、树突增殖、活动依赖性适应、技能学习和行为测试等结果的解释提供了潜在陷阱的实例。为人类试验设计提供信息的临床前实验理想情况下应包括反映人类疾病的病因、体积和位置的损伤；检查损伤附近和远处由损伤及修复程序引起的变化；区分反应性分子和组织学变化与对修复级联至关重要的变化；采用明确的训练范式来重新获得可测试的技能；将修复的形态学和生理学测量与任务重新获得的行为测量相关联；在不止一个实验室、不同品系或种类的啮齿动物以及更大的哺乳动物中重现关键结果；并将结果推广到多种疾病模型，如中风和脊髓损伤平台中的轴突再生。基础科学家和临床科学家在开发损伤与修复的转化动物模型方面的合作，可以推动符合伦理的从 bench 到 bedside 的治疗实验，以增强残疾患者的康复效果。
