Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative
Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative
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DOI：
10.3171/spi.2006.4.4.310
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发表时间：
2006-04-01
影响因子：
2.8
通讯作者：
Tomasello, F
中科院分区：
文献类型：
--
作者：
Grasso, G;Sfacteria, A;Tomasello, F
物体。脊髓损伤(SCI)是一种毁灭性的临床综合征，目前还没有真正有效的治疗方法。在临床前研究中，促红细胞生成素(EPO)及其非红细胞生成物asialoEPO和氨基甲酰化EPO在脊髓受压后应用可显著改善功能预后。然而，目前尚不清楚最佳的治疗模式。由于未损伤的脊髓在基础状态下表达高密度的EPO受体(EPOR)，因此在损伤前通过这些现有的受体传递信号可能具有神经保护作用，因此在预期损伤的情况下具有潜在的实用价值。作者将asialoEPO(一种与EPOR高亲和力但血清半衰期较短(t(1/2)<；2分钟)的分子)与EPO进行比较，以确定通过6周的神经结果评估和组织病理学分析，在脊髓受压1分钟前24小时静脉注射单次剂量(10微克/公斤体重)是否有好处。与用生理盐水处理的大鼠相比，用asialoEP0或EPO预处理的大鼠在42天内表现出改善的运动功能。然而，治疗效果比受伤时开始的治疗效果要差得多。在加压前立即采集的血清样本证实，体循环中没有检测到去唾液促红细胞生成素。Western印迹和免疫组织化学分析显示，给予asialo EPO 24小时后，未损伤的脊髓中胶质纤维酸性蛋白显著增加，提示EPO治疗后出现了胶质反应。这些结果表明，EPO及其类似物不需要在损伤时存在以提供组织保护，并且当两种药物中的任何一种在损伤后立即给予时，组织保护都是显著有效的。此外，研究结果表明，asialo EPO是研究EPO介导的神经保护动力学的有用试剂。此外，研究结果支持使用非促红细胞生成素的EPO衍生物在不激活EPO的不良影响的情况下提供组织保护的概念。
Object. Spinal cord injury (SCI) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its nonerythropoietic derivatives asialoEPO and carbamylated EPO have markedly improved functional outcome when administered after compressive SCI. However, an optimum treatment paradigm is currently unknown. Because the uninjured spinal cord expresses a high density of EPO receptor (EPOR) in the basal state, signaling through these existing receptors in advance of injury (pharmacological preconditioning) might confer neuroprotection and therefore be potentially useful in situations of anticipated damage.Methods. The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a brief serum half-life (t(1/2) < 2 minutes), to EPO to determine whether a single dose (10 mu g/kg of body weight) administered by intravenous injection 24 hours before I minute of spinal cord compression provides benefit as determined by a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEP0 or EPO and then subjected to a compressive injury exhibited improved motor function over 42 days, compared with animals treated with saline solution. However, pretreatment efficacy was substantially poorer than efficacy of treatment initiated at the time of injury. Serum samples drawn immediately before compression confirmed that no detectable asialoEPO remained within the systemic circulation. Western blot and immunohistochemical analyses performed using uninjured spinal cord 24 hours after a dose of asialoEPO exhibited a marked increase in glial fibrillary acidic protein, suggesting a glial response to EPO administration.Conclusions. These results demonstrate that EPO and its analog do not need to be present at the time of injury to provide tissue protection and that tissue protection is markedly effective when either agent is administered immediately after injury. Furthermore, the findings suggest that asialoEPO is a useful reagent with which to study the dynamics of EPO-mediated neuroprotection. In addition, the findings support the concept of using a nonerythropoietic EPO derivative to provide tissue protection without activating the undesirable effects of EPO.