Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse.
Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse.
复制标题
脑穿透性 IgG-促红细胞生成素融合蛋白对小鼠帕金森病进行静脉注射治疗后具有神经保护作用。
DOI：
10.1016/j.brainres.2011.01.061
复制
发表时间：
2011
期刊：
影响因子：
2.9
通讯作者：
Pardridge,WilliamM
中科院分区：
文献类型：
--
作者：
Zhou,Qing-Hui;Hui,EricKa-Wai;Lu,JeffZhiqiang;Boado,RubenJ;Pardridge,WilliamM
帕金森氏病（PD）是由氧化应激引起的，而促红细胞生成素（EPO）可降低大脑中的氧化应激。然而，EPO不能被开发为PD的治疗，因为EPO不能穿过血脑屏障（BBB）。已经开发了人EPO的脑穿透形式，其中EPO与针对小鼠转铁蛋白受体（TfR）的嵌合单克隆抗体（MAb）融合，其被命名为cTfRMAb-EPO融合蛋白。TfRMAb充当分子特洛伊木马，通过在BBB TfR上的转运将融合的EPO转运到脑中。通过纹状体内注射6-羟基多巴胺在成年小鼠中诱导实验性PD，并且从毒素注射后1小时开始，每隔一天用1 mg/kg的cTfRMAb-EPO融合蛋白静脉内（IV）处理PD小鼠。给药3周后，处死小鼠，测定纹状体酪氨酸羟化酶（TH）活性。用cTfRMAb-EPO融合蛋白治疗的小鼠显示纹状体TH酶活性增加306%，这与三项神经行为测定的改善相关。治疗2周时血细胞比容增加10%，治疗3周时无进一步变化。ELISA结果显示，重组融合蛋白的免疫反应呈低滴度、低滴度、易变性。总之，本研究表明，脑穿透形式的EPO在IV给药后对PD具有神经保护作用，对红细胞生成的影响最小。
Parkinson's disease (PD) is caused by oxidative stress, and erythropoietin (EPO) reduces oxidative stress in the brain. However, EPO cannot be developed as a treatment for PD, because EPO does not cross the blood–brain barrier (BBB). A brain penetrating form of human EPO has been developed wherein EPO is fused to a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), which is designated as the cTfRMAb-EPO fusion protein. The TfRMAb acts as a molecular Trojan horse to transport the fused EPO into brain via transport on the BBB TfR. Experimental PD was induced in adult mice by the intra-striatal injection of 6-hydroxydopamine, and PD mice were treated with 1mg/kg of the cTfRMAb-EPO fusion protein intravenously (IV) every other day starting 1 h after toxin injection. Following 3weeks of treatment mice were euthanized for measurement of striatal tyrosine hydroxylase (TH) enzyme activity. Mice treated with the cTfRMAb-EPO fusion protein showed a 306% increase in striatal TH enzyme activity, which correlated with improvement in three assays of neurobehavior. The blood hematocrit increased 10% at 2weeks, with no further changes at 3weeks of treatment. A sandwich ELISA showed the immune reaction against the cTfRMAb-EPO fusion protein was variable and low titer. In conclusion, the present study demonstrates that a brain penetrating form of EPO is neuroprotective in PD following IV administration with minimal effects on erythropoiesis.