Schneider Armin, Rogalewski Andreas, Wafzig Oliver, Kirsch Friederike, Gretz Norbert, Krüger Carola, Diederich Kai, Pitzer Claudia, Laage Rico, Plaas Christian, Vogt Gerhard, Minnerup Jens, Schäbitz Wolf-Rüdiger
SYGNIS Bioscience, Heidelberg, Germany.
Neurology Department Bethel EVKB Bielefeld and Dept. of Neurology, University of Muenster, Muenster, Germany.
Exp Transl Stroke Med. 2014 Feb 14;6(1):3. doi: 10.1186/2040-7378-6-3.
Both the immobilization of the unaffected arm combined with physical therapy (forced arm use, FAU) and voluntary exercise (VE) as model for enriched environment are promising approaches to enhance recovery after stroke. The genomic mechanisms involved in long-term plasticity changes after different means of rehabilitative training post-stroke are largely unexplored. The present investigation explored the effects of these physical therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia.
42 Wistar rats were randomly treated with either forced arm use (FAU, 1-sleeve plaster cast onto unaffected limb at 8/10 days), voluntary exercise (VE, connection of a freely accessible running wheel to cage), or controls with no access to a running wheel for 10 days starting at 48 hours after photothrombotic stroke of the sensorimotor cortex. Functional outcome was measured using sensorimotor test before ischemia, after ischemia, after the training period of 10 days, at 3 and 4 weeks after ischemia. Global gene expression changes were assessed from the ipsi- and contralateral cortex and the hippocampus.
FAU-treated animals demonstrated significantly improved functional recovery compared to the VE-treated group. Both were superior to cage control. A large number of genes are altered by both training paradigms in the ipsi- and contralateral cortex and the hippocampus. Overall, the extent of changes observed correlated well with the functional recovery obtained. One category of genes overrepresented in the gene set is linked to neuronal plasticity processes, containing marker genes such as the NMDA 2a receptor, PKC ζ, NTRK2, or MAP 1b.
We show that physical training after photothrombotic stroke significantly and permanently improves functional recovery after stroke, and that forced arm training is clearly superior to voluntary running training. The behavioral outcomes seen correlate with patterns and extent of gene expression changes in all brain areas examined. We propose that physical training induces a fundamental change in plasticity-relevant gene expression in several brain regions that enables recovery processes. These results contribute to the debate on optimal rehabilitation strategies, and provide a valuable source of molecular entry points for future pharmacological enhancement of recovery.
将未受影响的手臂固定与物理治疗相结合（强制使用手臂，FAU）以及将自愿运动（VE）作为丰富环境的模型，都是有望促进中风后恢复的方法。中风后不同康复训练方式引起的长期可塑性变化所涉及的基因组机制在很大程度上尚未得到探索。本研究探讨了这些物理治疗对实验性缺血后行为恢复和再生分子标志物的影响。
42只Wistar大鼠在感觉运动皮层光血栓形成性中风后48小时开始，随机接受强制使用手臂（FAU，在8/10天时用单袖石膏固定未受影响的肢体）、自愿运动（VE，将可自由使用的跑步轮连接到笼子）或10天内无法使用跑步轮的对照处理。在缺血前、缺血后、10天训练期后、缺血后3周和4周使用感觉运动测试测量功能结果。从同侧和对侧皮层以及海马评估全局基因表达变化。
与VE治疗组相比，FAU治疗的动物表现出明显改善的功能恢复。两者均优于笼子对照。同侧和对侧皮层以及海马中的大量基因在两种训练模式下均发生改变。总体而言，观察到的变化程度与获得的功能恢复密切相关。基因集中过度表达的一类基因与神经元可塑性过程相关，包含诸如NMDA 2a受体、PKC ζ、NTRK2或MAP 1b等标记基因。
我们表明，光血栓形成性中风后的体育训练可显著且永久性地改善中风后的功能恢复，并且强制手臂训练明显优于自愿跑步训练。观察到的行为结果与所有检查脑区中基因表达变化的模式和程度相关。我们提出体育训练会在几个脑区引起与可塑性相关基因表达的根本变化，从而促进恢复过程。这些结果有助于关于最佳康复策略的辩论，并为未来通过药物增强恢复提供了有价值分子切入点来源。
