Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston, Massachusetts 02115, USA.
J Neurosci. 2011 Apr 20;31(16):5977-88. doi: 10.1523/JNEUROSCI.4498-10.2011.
Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons' intrinsic growth potential by activating Mst3b, a component of the signal transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared with either treatment alone, and restored rats' level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.
中风是世界上许多地区导致残疾的主要原因，可用的治疗选择很少。在大鼠单侧中风后，肌苷，一种天然存在的嘌呤核苷，刺激来自未受损半球的突起生长进入脊髓去神经区域，并改善受损前肢的熟练使用。肌苷通过激活 Mst3b 来增强神经元的内在生长潜力，Mst3b 是调节轴突生长的营养因子信号转导途径的一部分。本研究调查了肌苷是否会补充通过其他机制促进可塑性的治疗的效果。在大鼠前肢运动区单侧中风后，肌苷与 NEP1-40（一种 Nogo 受体拮抗剂）联合使用，使从完整半球中的神经元延伸到脊髓去神经侧的轴突分支数量增加了一倍，与单独使用任何一种治疗相比，并且恢复了大鼠使用受损前爪进行术前水平的熟练抓取。当肌苷与环境富集（EE）联合使用时，也出现了类似的功能改善。后者的效果与受损皮质 5 层锥体神经元中的基因表达变化有关，这些变化远远超过了肌苷或 EE 单独作用的变化。肌苷目前正在进行其他适应症的临床试验，使其成为治疗中风患者的有吸引力的候选药物。
