Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats.
Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats.
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DOI：
10.3171/2011.3.jns101721
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发表时间：
2011-09
影响因子：
4.1
通讯作者：
Chopp M
中科院分区：
文献类型：
--
作者：
Meng Y;Xiong Y;Mahmood A;Zhang Y;Qu C;Chopp M
促红细胞生成素（EPO）延迟（伤后24小时）治疗可改善实验性创伤性脑损伤（TBI）后的功能恢复。在这项研究中，我们测试了延迟EPO治疗TBI的治疗效果是否是剂量依赖性的，试图建立延迟EPO治疗的最佳剂量范例。使用受控皮质撞击装置在麻醉的年轻成年雄性Wistar大鼠中进行实验性TBI。假手术组动物接受相同的手术程序，无损伤。动物（8只大鼠/组）在TBI后接受3次EPO（0、1000、3000、5000或7000 U/kg体重，在24、48和72小时）腹膜内注射。分别采用改良的神经系统严重程度评分、足错试验和Morris水迷宫试验评估感觉运动和认知功能。在损伤后35天处死动物，并对脑切片进行染色用于免疫组织化学分析。与生理盐水组相比，EPO 1000 ~ 7000 U/kg剂量组损伤体积无明显改变，但可显著减少海马神经元丢失，促进损伤皮质和海马的血管新生和神经发生，并显著改善感觉运动功能和空间学习能力。与较低或较高EPO剂量组相比，5000 U/kg的中等剂量组在组织学和功能结局方面表现出显著改善。这些数据表明，延迟（损伤后24小时）的EPO治疗提供了剂量依赖性神经恢复，这可能有助于改善TBI后的功能恢复，这意味着应用最佳剂量的EPO可能会增加成功的临床前和临床试验治疗TBI。
Delayed (24 hours post injury) treatment with erythropoietin (EPO) improves functional recovery following experimental traumatic brain injury (TBI). In this study, we tested whether therapeutic effects of delayed EPO treatment for TBI are dose-dependent in an attempt to establish an optimal dose paradigm for the delayed EPO treatment. Experimental TBI was performed in anesthetized young adult male Wistar rats using a controlled cortical impact device. Sham animals underwent the same surgical procedure without injury. The animals (8 rats/group) received 3 intraperitoneal injections of EPO (0, 1000, 3000, 5000 or 7000 U/kg body weight, at 24, 48 and 72 hours) after TBI. Sensorimotor and cognitive functions were assessed using a modified neurological severity score and foot fault test, and Morris water maze tests, respectively. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemical analyses. Compared to the saline treatment, EPO treatment at doses from1000 to 7000 U/kg did not alter lesion volume but significantly reduced hippocampal neuron loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved sensorimotor function and spatial learning. The medium dose at 5000 U/kg exhibited a significant improvement in histological and functional outcomes compared with the lower or higher EPO dose groups. These data demonstrate that delayed (24 hours post injury) treatment with EPO provides dose-dependent neurorestoration which may contribute to improved functional recovery after TBI, implying that application of an optimal dose of EPO is likely to increase successful preclinical and clinical trials for treatment of TBI.