Dachir Shlomit, Shabashov Dalia, Trembovler Victoria, Alexandrovich Alexander G, Benowitz Larry I, Shohami Esther
Department of Pharmacology, Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
Department of Pharmacology, Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Brain Res. 2014 Mar 25;1555:78-88. doi: 10.1016/j.brainres.2014.01.044. Epub 2014 Feb 3.
Despite years of research, no effective therapy is yet available for the treatment of traumatic brain injury (TBI). The most prevalent and debilitating features in survivors of TBI are cognitive deficits and motor dysfunction. A potential therapeutic method for improving the function of patients following TBI would be to restore, at least in part, plasticity to the CNS in a controlled way that would allow for the formation of compensatory circuits. Inosine, a naturally occurring purine nucleoside, has been shown to promote axon collateral growth in the corticospinal tract (CST) following stroke and focal TBI. In the present study, we investigated the effects of inosine on motor and cognitive deficits, CST sprouting, and expression of synaptic proteins in an experimental model of closed head injury (CHI). Treatment with inosine (100 mg/kg i.p. at 1, 24 and 48 h following CHI) improved outcome after TBI, significantly decreasing the neurological severity score (NSS, p<0.04 vs. saline), an aggregate measure of performance on several tasks. It improved non-spatial cognitive performance (object recognition, p<0.016 vs. saline) but had little effect on sensorimotor coordination (rotarod) and spatial cognitive functions (Y-maze). Inosine did not affect CST sprouting in the lumbar spinal cord but did restore levels of the growth-associated protein GAP-43 in the hippocampus, though not in the cerebral cortex. Our results suggest that inosine may improve functional outcome after TBI.
尽管经过多年研究，但目前仍没有有效的疗法可用于治疗创伤性脑损伤（TBI）。TBI幸存者中最常见且使人衰弱的特征是认知缺陷和运动功能障碍。一种潜在的改善TBI患者功能的治疗方法是，以可控的方式至少部分恢复中枢神经系统（CNS）的可塑性，从而允许形成代偿性回路。肌苷是一种天然存在的嘌呤核苷，已被证明在中风和局灶性TBI后可促进皮质脊髓束（CST）中的轴突侧支生长。在本研究中，我们在闭合性颅脑损伤（CHI）实验模型中研究了肌苷对运动和认知缺陷、CST发芽以及突触蛋白表达的影响。肌苷治疗（在CHI后1、24和48小时腹腔注射100 mg/kg）改善了TBI后的结果，显著降低了神经严重程度评分（NSS，与生理盐水组相比p<0.04），这是几项任务表现的综合指标。它改善了非空间认知表现（物体识别，与生理盐水组相比p<0.016），但对感觉运动协调（转棒试验）和空间认知功能（Y迷宫）影响不大。肌苷不影响腰脊髓中的CST发芽，但确实恢复了海马体中生长相关蛋白GAP-43的水平，不过在大脑皮层中没有恢复。我们的结果表明，肌苷可能改善TBI后的功能结局。
