Koike H, Ishida A, Shimamura M, Mizuno S, Nakamura T, Ogihara T, Kaneda Y, Morishita R
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Gene Ther. 2006 Dec;13(23):1639-44. doi: 10.1038/sj.gt.3302810. Epub 2006 Jun 22.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.
帕金森病（PD）是一种神经退行性疾病，其特征是黑质（SNi）中多巴胺能神经元的丧失。由于神经营养因子支持多巴胺能神经元的存活并增强其功能，使用神经营养因子的基因治疗已成为研究热点。因此，我们将重点放在肝细胞生长因子（HGF）上，它是一种神经营养和血管生成生长因子。在向SNi注射6-羟基多巴胺前7天，将人HGF或lacZ质粒立体定向转染到大鼠单侧纹状体中。使用免疫组织化学染色，在转染HGF质粒DNA的大鼠中可检测到注射部位人HGF的表达。同样，在转染后至少12天可检测到具有人免疫反应性的HGF蛋白。有趣的是，转染lacZ的帕金森病大鼠表现出苯丙胺诱导的旋转不对称。然而，转染HGF质粒DNA导致异常旋转在长达24周的时间内以剂量依赖的方式受到显著抑制。通过免疫组织化学染色评估，转染lacZ的帕金森病大鼠中超过90%的多巴胺能神经元丧失，而转染HGF的大鼠中有超过70%存活。总体而言，本研究表明HGF的过表达可防止帕金森病大鼠模型中的神经元死亡，为帕金森病提供了一种潜在的新疗法。
