Grasso Giovanni, Sfacteria Alessandra, Erbayraktar Serhat, Passalacqua Marcello, Meli Francesco, Gokmen Necati, Yilmaz Osman, La Torre Domenico, Buemi Michele, Iacopino Domenico G, Coleman Thomas, Cerami Anthony, Brines Michael, Tomasello Francesco
Department of Neurosurgery, University of Palermo, Italy.
J Neurosurg Spine. 2006 Apr;4(4):310-8. doi: 10.3171/spi.2006.4.4.310.
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.
The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a brief serum half-life (t1/2 < 2 minutes), to EPO to determine whether a single dose (10 microg/kg of body weight) administered by intravenous injection 24 hours before 1 minute of spinal cord compression provides benefit as determined by a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEPO 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.
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.
脊髓损伤（SCI）是一种极具破坏性的临床综合征，目前尚未找到真正有效的治疗方法。在临床前研究中，促红细胞生成素（EPO）及其非促红细胞生成衍生物去唾液酸促红细胞生成素（asialoEPO）和氨甲酰化促红细胞生成素（carbamylated EPO）在压迫性脊髓损伤后给药时，能显著改善功能结局。然而，目前尚不清楚最佳治疗模式。由于未受伤的脊髓在基础状态下表达高密度的促红细胞生成素受体（EPOR），在损伤前通过这些现有受体进行信号传导（药理预处理）可能赋予神经保护作用，因此在预期损伤的情况下可能有用。
作者将去唾液酸促红细胞生成素（一种与EPOR具有高亲和力但血清半衰期较短（t1/2 < 2分钟）的分子）与促红细胞生成素进行比较，以确定在脊髓压迫1分钟前24小时静脉注射单剂量（10微克/千克体重）是否能通过6周的神经功能结局评估和组织病理学分析带来益处。与用盐溶液处理的动物相比，用去唾液酸促红细胞生成素或促红细胞生成素预处理后再遭受压迫性损伤的大鼠在42天内运动功能得到改善。然而，预处理的效果远不如损伤时开始治疗的效果。压迫前立即采集的血清样本证实，全身循环中已检测不到去唾液酸促红细胞生成素。在给予一剂去唾液酸促红细胞生成素24小时后，对未受伤的脊髓进行蛋白质印迹和免疫组织化学分析，结果显示胶质纤维酸性蛋白显著增加，表明胶质细胞对促红细胞生成素给药有反应。
这些结果表明，促红细胞生成素及其类似物在损伤时不需要存在就能提供组织保护，并且当在损伤后立即给予这两种药物中的任何一种时，组织保护作用都非常有效。此外，研究结果表明去唾液酸促红细胞生成素是研究促红细胞生成素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的促红细胞生成素衍生物来提供组织保护而不激活促红细胞生成素不良影响的概念。
