Department of Medicine, UCLA, Los Angeles, CA 90024, USA.
Brain Res. 2011 Jan 19;1369:203-7. doi: 10.1016/j.brainres.2010.10.097. Epub 2010 Oct 31.
Erythropoietin (EPO) is a potential new treatment for acute stroke. However, EPO does not cross the blood-brain barrier (BBB). EPO has been re-engineered as an IgG-EPO fusion protein, where EPO is fused to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), which is designated the cTfRMAb-EPO fusion protein. The re-engineered EPO is able to penetrate the BBB following intravenous (IV) administration owing to transport on the BBB TfR. In the present study, the neuroprotective properties of EPO alone and the cTfRMAb-EPO fusion protein following IV injection were investigated in a permanent middle cerebral artery occlusion (MCAO) model in the adult mouse. Following MCAO, mice were treated IV with low (1000 U/kg) and high (10,000 U/kg) doses of recombinant EPO, or with low (0.05 mg/kg) or high (1.0 mg/kg) doses of the cTfRMAb-EPO fusion protein. Hemispheric stroke volume and neural deficit scores were quantitated 24h after MCAO. There was no reduction in stroke volume or neural deficit following the IV administration of either dose of EPO or the low dose of cTfRMAb-EPO fusion protein. However, after treatment with the 1.0 mg/kg dose of the cTfRMAb-EPO fusion protein, the hemispheric stroke volume was reduced 81% and the neural deficit was reduced 78%. These studies demonstrate high degrees of neuroprotection in stroke with EPO when the neurotrophin is re-engineered as an IgG-EPO fusion protein to enable transport across the BBB following IV administration.
促红细胞生成素（EPO）是一种治疗急性中风的新方法。然而，EPO 无法穿过血脑屏障（BBB）。EPO 已被重新设计为 IgG-EPO 融合蛋白，其中 EPO 融合到针对小鼠转铁蛋白受体（TfR）的嵌合单克隆抗体（MAb）的重链上，该 MAb 被指定为 cTfRMAb-EPO 融合蛋白。经过改造的 EPO 能够在静脉内（IV）给药后穿透 BBB，这是由于 BBB TfR 上的转运。在本研究中，研究了单独给予 EPO 以及在成年小鼠的永久性大脑中动脉闭塞（MCAO）模型中静脉内注射 cTfRMAb-EPO 融合蛋白后的神经保护特性。MCAO 后，用低（1000U/kg）和高（10000U/kg）剂量的重组 EPO，或用低（0.05mg/kg）或高（1.0mg/kg）剂量的 cTfRMAb-EPO 融合蛋白经 IV 治疗。MCAO 后 24 小时定量半球性卒中体积和神经缺陷评分。两种剂量的 EPO 或低剂量的 cTfRMAb-EPO 融合蛋白的 IV 给药均未减少卒中体积或神经缺陷。然而，在用 1.0mg/kg 剂量的 cTfRMAb-EPO 融合蛋白治疗后，半球性卒中体积减少了 81％，神经缺陷减少了 78％。这些研究表明，当神经生长因子被重新设计为 IgG-EPO 融合蛋白以在 IV 给药后能够穿透 BBB 时，EPO 在中风中具有高度的神经保护作用。
