Control of dopamine-secretion by Tet-Off system in an in vivo model of parkinsonian rat
Control of dopamine-secretion by Tet-Off system in an in vivo model of parkinsonian rat
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DOI：
10.1016/j.brainres.2006.04.078
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发表时间：
2006-08-02
期刊：
影响因子：
2.9
通讯作者：
Date, Isao
中科院分区：
文献类型：
--
作者：
Kobayashi, Kazuki;Yasuhara, Takao;Date, Isao
我们建立了 PC12 细胞系 (PC12TH Tet-Off)，其中人酪氨酸羟化酶 (TH) 的表达可以受到多西环素 (Dox) 的负控制。首先，在体外以0至100ng/ml的剂量响应方式施用Dox来控制PC12TH Tet-Off细胞的多巴胺(DA)分泌70天。此外，与未给予Dox的移植大鼠相比，接受封装的PC12TH Tet-Off细胞的大鼠的帕金森病模型显示脑脊液（CSF）中的多巴胺浓度显着降低，并且与未给予Dox的移植大鼠相比，通过Dox给予的阿朴吗啡诱导的旋转次数增加，尽管随着时间的推移认识到给予Dox的CSF中DA浓度的降低率显着降低。植入后 2 个月，植入的纹状体和取出的胶囊中的多巴胺浓度表明，在体内 2 个月内可以部分实现对 DA 分泌的控制。我们的结果支持了使用 Tet-Off 系统的细胞治疗的价值，并且封装技术可能是治疗帕金森病的一种可行选择，特别是在解决未来多巴胺供应过剩的问题方面，尽管在临床应用之前应该探索一种更有效的方法来控制 DA 分泌，通过更快的调节和更多的剂量滴定。 (c) 2006 Elsevier B.V. 保留所有权利。
We established a PC12 cell line (PC12TH Tet-Off) in which human tyrosine hydroxylase (TH) expression can be negatively controlled by Doxycycline (Dox). First, dopamine (DA)secretion from PC12TH Tet-Off cells was controlled by Dox-administration in a dose-responsive manner ranging from 0 to 100 ng/ml for 70 days in vitro. Furthermore, Parkinson's disease model of rats receiving encapsulated PC12TH Tet-Off cells displayed a significant decrease of dopamine concentration in the cerebrospinal fluid (CSF) and increase of the number of apomorphine-induced rotations by Dox-administration, as compared to transplanted rats without Dox-administration, although the significant decrease of the reduction ratio of DA concentration in the CSF with Dox-administration was recognized over time. At 2 months post-implantation, concentration of dopamine in the implanted striatum and from the retrieved capsules demonstrated that the control of DA-secretion could be partially achieved for 2 months in vivo. Our results support both the value of cell therapy using Tet-Off system and the technique of encapsulation might be a feasible option for Parkinson's disease especially in resolving the problem of dopamine oversupply in the future, although a more efficient way to control DA-secretion with quicker regulation and much titration of dose should be explored before clinical application. (c) 2006 Elsevier B.V. All rights reserved.