Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo
Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo
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DOI：
10.1073/pnas.1031753100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Brines, M
中科院分区：
文献类型：
--
作者：
Erbayraktar, S;Grasso, G;Brines, M
促红细胞生成素（EPO）是一种组织保护性细胞因子，可预防血管痉挛、细胞凋亡和炎症反应。虽然EPO以其在造血谱系中的作用而闻名，但它也影响其他组织，包括神经系统。然而，对重组人促红细胞生成素（rhEPO）作为一种潜在的神经保护治疗药物的热情必须有所缓和，因为它也会增加循环红细胞质量和血小板聚集性。在这里，我们研究了rhEPO的红细胞生成和组织保护活性是否可能通过分子的变异分离。我们证明，asialoEPO （asialoEPO）是由rhEPO的总酶脱氮产生的，具有非常短的血浆半衰期，并具有完全的神经保护作用。与rhEPO形成鲜明对比的是，该分子在rhEPO表现出红细胞生成的剂量和频率下，没有增加小鼠或大鼠的红细胞压积。静脉给药后脑脊液内迅速出现AsialoEPO；静脉注射放射性碘标记的asialoEPO以与EPO受体分布相对应的模式结合在海马和皮层内的神经元上。最重要的是，asialoEPO在脑缺血、脊髓压迫和坐骨神经挤压模型中显示出广泛的神经保护活性。这些数据表明rhEPO的非红细胞生成变体可以穿过血脑屏障并提供神经保护。
Erythropoietin (EPO) is a tissue-protective cytokine preventing vascular spasm, apoptosis, and inflammatory responses. Although best known for its role in hematopoietic lineages, EPO also affects other tissues, including those of the nervous system. Enthusiasm for recombinant human erythropoietin (rhEPO) as a potential neuroprotective therapeutic must be tempered, however, by the knowledge it also enlarges circulating red cell mass and increases platelet aggregability. Here we examined whether erythropoietic and tissue-protective activities of rhEPO might be dissociated by a variation of the molecule. We demonstrate that asialoerythropoietin (asialoEPO), generated by total enzymatic desialylation of rhEPO, possesses a very short plasma half-life and is fully neuroprotective. In marked contrast with rhEPO, this molecule at doses and frequencies at which rhEPO exhibited erythropoiesis, did not increase the hematocrit of mice or rats. AsialoEPO appeared promptly within the cerebrospinal fluid after i.v. administration; intravenously administered radioiodine-labeled asialoEPO bound to neurons within the hippocampus and cortex in a pattern corresponding to the distribution of the EPO receptor. Most importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood-brain barrier and provide neuroprotection.