Intravenous treatment of experimental Parkinson's disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood-brain barrier.
Intravenous treatment of experimental Parkinson's disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood-brain barrier.
复制标题
DOI：
10.1016/j.brainres.2010.06.059
复制
发表时间：
2010-09-17
期刊：
影响因子：
2.9
通讯作者：
Pardridge WM
中科院分区：
文献类型：
--
作者：
Fu A;Zhou QH;Hui EK;Lu JZ;Boado RJ;Pardridge WM
胶质源性神经营养因子（GDNF）是实验性帕金森病（PD）黑质-纹状体束的营养因子。神经营养因子必须通过脑内注射给药，因为GDNF不能穿过血脑屏障（BBB）。在本研究中，GDNF被重新工程化，以使受体介导的运输通过血脑屏障后融合的GDNF嵌合单克隆抗体（MAb）的重链对小鼠转铁蛋白受体（TfR），这种融合蛋白被命名为cTfRMAb-GDNF。该融合蛋白先前已显示对GDNF受体和小鼠TfR两者保持低nM结合常数，并且在静脉内给药后迅速进入小鼠体内脑。通过纹状体内注射6-羟基多巴胺诱导小鼠中的实验PD，并且从毒素注射后1小时开始，每隔一天用盐水或cTfRMAb-GDNF融合蛋白处理小鼠3周。融合蛋白治疗引起阿扑吗啡诱导的旋转减少44%，安非他明诱导的旋转减少45%，触须引起的前肢放置试验增加121%，纹状体酪氨酸羟化酶（TH）酶活性增加272%，在毒素注射后3周。融合蛋白治疗没有引起对侧纹状体或额叶皮质TH酶活性的变化。总之，GDNF与BBB分子特洛伊木马融合后，在静脉内给药后观察到GDNF在实验性PD脑中的营养作用。
Glial derived neurotrophic factor (GDNF) is a trophic factor for the nigra-striatal tract in experimental Parkinson’s disease (PD). The neurotrophin must be administered by intra-cerebral injection, because GDNF does not cross the blood-brain barrier (BBB). In the present study, GDNF was re-engineered to enable receptor-mediated transport across the BBB following fusion of GDNF to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-GDNF. This fusion protein had been previously shown to retain low nM binding constants for both the GDNF receptor and the mouse TfR, and to rapidly enter the mouse brain in vivo following intravenous administration. Experimental PD in mice was induced by the intra-striatal injection of 6-hydroxydopamine, and mice were treated with either saline or the cTfRMAb-GDNF fusion protein every other day for 3 weeks, starting 1 hour after toxin injection. Fusion protein treatment caused a 44% decrease in apomorphine-induced rotation, a 45% reduction in amphetamine-induced rotation, a 121% increase in the vibrissae-elicited forelimb placing test, and a 272% increase in striatal tyrosine hydroxylase (TH) enzyme activity at 3 weeks after toxin injection. Fusion protein treatment caused no change in TH enzyme activity in either the contralateral striatum or the frontal cortex. In conclusion, following fusion of GDNF to a BBB molecular Trojan horse, GDNF trophic effects in brain in experimental PD are observed following intravenous administration.
登录
查看更多内容
影响因子：
3.8
作者：
Boado, Ruben J.;Zhang, Yun;Wang, Yuntao;Pardridge, William M.
通讯作者：
Pardridge, William M.
影响因子：
3.9
作者：
Boado, Ruben J.;Pardridge, William M.
通讯作者：
Pardridge, William M.
影响因子：
2.5
作者：
Cheng, Qingzhang;Di Liberto, Valentina;Mudo, Giuseppa
通讯作者：
Mudo, Giuseppa
影响因子：
3.9
作者：
Zhou, Qing-Hui;Boado, Ruben J.;Pardridge, William M.
通讯作者：
Pardridge, William M.
影响因子：
3.3
作者：
Lapchak, PA;Miller, PJ;Jiao, S
通讯作者：
Jiao, S