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首页> 外文期刊>Biotechnology Progress >Isolation and Characterization of a Subset of Erythropoietin Glycoforms with Cytoprotective but Minimal Erythropoietic Activity
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Isolation and Characterization of a Subset of Erythropoietin Glycoforms with Cytoprotective but Minimal Erythropoietic Activity

机译：具有细胞保护性但最小的促红细胞生成活性的促红细胞生成素糖型亚型的分离和鉴定

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Although historically used for the treatment of anemia, erythropoietin (EPO) has emerged as a neurotrophic and neuroprotective agent in different conditions of neuronal damage (traumatic brain injury, ischemia, spinal cord compression, peripheral neuropathy, retinal damage, epilepsy, Parkinson s Disease, among others). Nonetheless, EPO's therapeutic application is limited due to its hematological side-effects. With the aim of obtaining EPO derivatives resembling the hormone isolated from cells and tissues of neural origin, a novel combination of less acidic EPO glycoforms -designated as neuroepoetin (rhNEPO)- was purified to homogeneity from the supernatant of a CHO-producing cell line by a four-step chromatographic procedure. This simple and single process allowed us to prepare two EPO derivatives with distinct therapeutic expectations: the hematopoietic version and a minimally hematopoietic, but mainly in vitro cytoprotective, alternative. Further biological characterization showed that the in vivo erythropoietic activity of rhNEPO was 25-times lower than that of rhEPO. Interestingly, using different in vitro cytoprotective assays we found that this molecule exerts cytoprotection equivalent to, or better than, that of rhEPO in cells of neural phenotype. Furthermore, despite its shorter plasma half-life, rhNEPO was rapidly absorbed and promptly detected in the cerebrospinal fluid after intravenous administration in rats (5 min postinjection, in comparison with 30 min for rhEPO). Therefore, our results support the study of neuroepoetin as a potential drug for the treatment of neurological diseases, combining high cytoprotective activity with reduced hematological side-effects.
机译：尽管促红细胞生成素（EPO）在历史上曾用于治疗贫血，但已在各种神经元损伤（颅脑损伤，局部缺血，脊髓压迫，周围神经病变，视网膜损伤，癫痫，帕金森氏病，等等）。尽管如此，由于其血液学副作用，EPO的治疗应用受到限制。为了获得类似于从神经源细胞和组织中分离出的激素的EPO衍生物，通过从CHO生产细胞系的上清液中纯化出酸性较低的EPO糖型（称为神经上皮素（rhNEPO））的新组合，使其具有同质性。四步色谱程序。这个简单而单一的过程使我们能够制备出具有不同治疗期望的两种EPO衍生物：造血形式和最小限度的造血作用，但主要是体外细胞保护作用的替代物。进一步的生物学表征表明，rhNEPO的体内促红细胞生成活性比rhEPO低25倍。有趣的是，使用不同的体外细胞保护性检测方法，我们发现该分子在神经表型细胞中发挥的细胞保护作用相当于或优于rhEPO。此外，尽管其血浆半衰期较短，但在大鼠静脉内给药后（注射后5分钟，而rhEPO为30分钟），rhNEPO被迅速吸收并迅速在脑脊液中检测到。因此，我们的结果支持神经表皮素作为治疗神经系统疾病的潜在药物的研究，将高细胞保护活性与降低的血液学副作用相结合。

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