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Studies on specific genes in the brain induced by DOPA and their function.

多巴诱导的大脑特定基因及其功能的研究。

基本信息

批准号：
14570599
负责人：
OGAWA Norio
金额：
$ 2.24万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

To clarify the molecular events in the brain of parkinsonian who treated with levodopa of anti-parkinsonian drugs, we investigated the genes in the nigrostriatal pathway of parkinsonian model animals specifically induced by levodopa treatment, and also analyzed their function, as follows :1.Screening of expressed genes in the brain of parkinsonian models after levodopa treatmentWe screened the specific genes which expressed in the striatum of hemi-parkinsonian model rats after levodopa treatment by using differential display method. A proapoptotic gene, p53-activated gene 608(PAG608) was identified as a DOPA-induced gene in parkinsonian brain.2.Role of PAG608 in oxidative stress-induced apoptosis in dopaminergic neuronal cellsIn the catecholaminergic cells, inhibition of PAG608 expression by the transfection with antisense PAG608 cDNA blocked 6-hydroxydopamine-or hydrogen peroxide-induced cell death, increases in p53 and Bax expression, reduction of mitochondrial membrane potential, ac … More tivation of caspase-3 and DNA fragmentation. Although PAG608 is activated by p53, overexpression of PAG608 by the transfection of PAG608 gene inversely increased p53 expression. Furthermore, we clarified that the translocation of PAG608 to the nucleus and nucleolus is necessary for induction of apoptosis.3.Involvement of PAG608 in_dopamine-or methamphetamine-induced neurotoxicityThe inhibition of PAG608 expression by the transfection with antisense PAG608 cDNA also blocked excess dopamine-or methamphetamine-induced dopaminergic cell death and their apoptotic morphological changes.4.Expression of PAG608 in the brain of levodopa-treated parkinsonian model ratsPAG608 constitutively expressed in the pontine nucleus, motor nuclei of trigeminal nerve and facial nerve. In the internal capsule, PAG608 expression was strongly induced in the parkinsonian side of levodopa-treated group.These experimental results suggest that PAG608 is generally involved in the common pathway of dopaminergic neuronal death induced by the treatment of levodopa or methamphetamine and that it is a molecule specifically induced by excess amount of dopamine in the basal ganglia of parkinsonian models. Less

为了阐明抗帕金森病药物左旋多巴治疗后脑内的分子事件，我们对左旋多巴治疗特异性诱导的帕金森病模型动物黑质纹状体通路中的基因进行了研究，并对其功能进行了分析，如下：1.左旋多巴治疗后帕金森病模型脑内表达基因的筛选我们筛选了表达的特异基因。采用差异显示法观察左旋多巴治疗后的半侧帕金森病模型大鼠纹状体。帕金森病脑中发现促凋亡基因p53激活基因608（PAG608）是多巴诱导的基因。2.PAG608在氧化应激诱导的多巴胺能神经元细胞凋亡中的作用在儿茶酚胺能细胞中，转染反义PAG608 cDNA抑制PAG608的表达阻断 6-羟基多巴胺或过氧化氢诱导的细胞死亡，增加 p53 和 Bax 表达，降低线粒体膜电位，激活 caspase-3 和 DNA 片段化。尽管PAG608被p53激活，但是通过转染PAG608基因而过度表达PAG608反而增加了p53的表达。此外，我们还阐明PAG608易位到细胞核和核仁对于诱导细胞凋亡是必要的。3.PAG608参与多巴胺或甲基苯丙胺诱导的神经毒性转染反义PAG608 cDNA抑制PAG608表达也阻断了过量的多巴胺或甲基苯丙胺诱导的神经毒性。甲基苯丙胺诱导的多巴胺能细胞死亡及其凋亡形态学变化。4.左旋多巴帕金森病模型大鼠脑内PAG608的表达PAG608在脑桥核、三叉神经运动核和面神经中组成型表达。在内囊中，左旋多巴治疗组的帕金森病一侧强烈诱导PAG608表达。这些实验结果表明，PAG608普遍参与了左旋多巴或甲基苯丙胺治疗诱导的多巴胺能神经元死亡的共同途径，并且它是在基底节中特异性诱导过量多巴胺的分子。帕金森模型。较少的