Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis
Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis
复制标题
DOI：
10.1016/j.jneuroim.2005.10.016
复制
发表时间：
2006-03-01
影响因子：
3.3
通讯作者：
Bianchi, R
中科院分区：
文献类型：
--
作者：
Savino, C;Pedotti, R;Bianchi, R
促红细胞生成素（EPO）介导广泛的神经保护活性，包括改善EAE大鼠模型的疾病和神经炎症。然而，目前尚不清楚最佳关闭参数。在本研究中，我们使用了一种通过用髓鞘少突胶质细胞糖蛋白肽（MOG（35-55））免疫诱导的小鼠慢性EAE模型，以比较不同治疗方案给予EPO的效果。从免疫后第3天（预防方案）、临床疾病发作时（治疗方案）或症状发作后15天（晚期治疗方案）开始，每周三次以0.5、5.0或50 μ g/kg腹腔内施用EPO。结果表明，EPO是有效的，即使在EAE的临床症状出现后给予，但与预防性方案相比，其功效降低。为了确定这种作用是否需要EPO的同型二聚体EPO受体（EPOR 2）介导的造血作用，我们研究了不结合EPOR 2的氨甲酰化EPO（CEPO）的作用。CEPO可改善EAE，而不改变血红蛋白浓度。另一种非红细胞生成衍生物，脱唾液酸EPO也有效。EPO和CEPO均能同等程度地降低脊髓中TNF-α、IL-1 β和IL-1 Ra以及外周淋巴细胞IFN-γ的EAE相关产生，表明它们的作用涉及靶向神经炎症。试验的最低剂量似乎完全有效。将EPO的抗神经炎症作用与其造血作用分离的可能性（其可能在非贫血患者中引起不期望的副作用）为多发性硬化症的治疗提供了新的途径。(C)2005 Elsevier B.V保留所有权利。
Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum closing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the rnyelin oligodendrocyte glycoprotein peptide (MOG(35-55)) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 mu g/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR2)-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR2. CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-alpha, IL-1 beta and IL-1Ra in the spinal cord, and IFN-gamma by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis. (C) 2005 Elsevier B.V All rights reserved.