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Molecular pathophysiology of dopamine receptors in dyskinesia

运动障碍多巴胺受体的分子病理生理学

基本信息

批准号：
04670489
负责人：
OGAWA Norio
金额：
$ 1.34万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

In the animal model of dyskinesia, molecular, chemical and pharmacological studies were conducted before and after modification of dyskinetic symptoms. Results were :(1) In the iminodipropionitrile (IDPN) -induced dyskinesia model, dopamine turnover, dopamine D1-receptor (R), D2-R,D1-R mRNA and D2-R mRNA were reduced.Chronic administration of ceruletide normalized these biochemical changes. Immunosuppressant cyclosporine A (CsA) accelerated IDPN-induced dyskinesia in behavioraly and biochemicaly.(2) In electrophoretic mobility shift assay, CsA increased cAMP response element (CRE) binding activity in the various brain regions compared with that in the IDPN treatment alone.(3) From the results of neuropeptide levels of IDPN-treated rat brain, neuropeptides in the basal ganglia, hindbrain and cerebral cortex may play important roles in the manifestation of dyskinetic symptoms.(4) Striatal c-fos mRNA expression was under the control of muscarinic cholinergic receptor mechanis.(5) In vitro cultured neuronal cells, both DNA-binding activities of AP-1 and CREB markedly decreased with 6-OHDA and H_2O_2.While in the cultured glial cells, the AP-1 binding activity was increased with 6-OHDA and H_2O_2. In vivo study, persistent increase of DNA-binding activity of AP-1 was observed in the striatum of 6-OHDA icv-injected mice even 1 week after injection.Administration of immunosuppressant FK506 corrected this increased AP-1 activity to the control levels.Thus, immune response might be involved in pathogenesis and pathophysiology of dyskinesia through modulation of transcription factors of genes.

在运动障碍的动物模型中，在运动障碍症状改变之前和之后进行分子、化学和药理学研究。结果表明：（1）在亚氨基二丙腈（IDPN）诱导的运动障碍模型中，多巴胺转换率、多巴胺D1受体（R）、D2受体、D1受体mRNA和D2受体mRNA均降低，长期应用蓝鲸肽可使这些生化变化恢复正常。免疫抑制剂环孢霉素A（CsA）在行为学和生化学上加速IDPN诱导的运动障碍。(2)在电泳迁移率变动分析中，CsA增加cAMP反应元件（CRE）结合活性的各个脑区相比，在IDPN单独治疗。(3)从IDPN处理的大鼠脑内神经肽水平的结果来看，基底节、后脑和大脑皮质的神经肽可能在运动障碍症状的表现中起重要作用。(4)纹状体c-fos mRNA的表达受M胆碱能受体机制的调控。(5)在体外培养的神经元细胞中，6-OHDA和H_2O_2均能显著降低AP-1和CREB的DNA结合活性，而在体外培养的神经胶质细胞中，6-OHDA和H_2O_2则能增强AP-1的DNA结合活性。在体内研究中，icv注射6-OHDA的小鼠纹状体内AP-1的DNA结合活性在注射后1周仍持续升高，给予免疫抑制剂FK 506后，AP-1活性的升高被纠正至对照水平，因此，免疫应答可能通过调节基因转录因子参与了运动障碍的发病和病理生理过程。