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Molecular function of metallothionein-III in parkinsonism with drug treatment

金属硫蛋白-III在帕金森病药物治疗中的分子功能

基本信息

批准号：
11670629
负责人：
OGAWA Norio
金额：
$ 2.11万
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：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

To clarify the function, role and involvement of metallothionein (MT), especially MT-III, in parkinsonian and aged, we investigated the expression and function of MT-III, and changes in MT with the treatment of dopaminergic drugs, oxidative stress and aging, as follows:1. Expression of MT-III mRNA in the brain of animal models of Parkinson's diseaseLevodopa-induced increase in MT-III mRNA which shown in the contralateral side of the striatum was not seen in the ipsilateral side of the striatum in hemi-parkinsonian rats which lesioned by 6-hydroxydopamine (6-OHDA), suggesting that low inducibility of MT-III by levodopa treatment in the parkinsonian brain aggravates the disease through generation of oxidative stress.2. Effects of aging and inflammatory stress on MT-III expression in the brainThe treatment of an endotoxin lipopolysaccaride which produces inflammation markedly induced increases in MT-III expression, especially in the oligodendroglial cells and the microglial cells, in the young-adult rat brain regions. However, the treatment of the toxin did not increase rather suppress MT-III expression in the aged rat brain, suggesting that the responsibility of brain MT-III against oxidative stress is decreased as aging.3. MT-III expression and its subcellular localization in the differenciated dopaminergic cellsThe treatment of differentiating reagent increased MT-III expression in dopaminergic cells. Furthermore, we clarified that MT-III was translocated into the nucleus in the differentiated dopaminergic cells when additional treatment of brain extract produced apoptotic cell death.4. Dopaminergic lesions by 6-OHDA in metallothionein-I and -II knock-out mice brainThe loss of nigral dopamine neurons induced by the 6-OHDA injection was significantly aggravated in the MT-I, II knock-out mice, suggest that MT-I and -II exert neuroprotective effects against the dopaminergic neurotoxicity of 6-OHDA in the substantia nigra.

为了阐明金属硫蛋白（MT），特别是MT- iii在帕金森病和老年中的功能、作用和参与，我们研究了MT- iii的表达和功能，以及MT在多巴胺能药物、氧化应激和衰老治疗中的变化。在6-羟多巴胺（6-OHDA）损伤的半帕金森大鼠中，左旋多巴诱导的对侧纹状体MT-III mRNA表达增加在同侧纹状体中未见，提示左旋多巴对帕金森大脑MT-III的低诱导性通过氧化应激的产生加重了疾病。衰老和炎症应激对脑内MT-III表达的影响产生炎症的内毒素脂多糖的处理显著诱导MT-III表达的增加，特别是在年轻成年大鼠脑区域的少突胶质细胞和小胶质细胞中。然而，毒素的处理并没有增加而是抑制MT-III在老年大鼠脑中的表达，这表明脑MT-III抗氧化应激的作用随着年龄的增长而降低。MT-III在多巴胺能分化细胞中的表达及其亚细胞定位分化试剂的处理增加了MT-III在多巴胺能分化细胞中的表达。此外，我们澄清了MT-III在分化的多巴胺能细胞中易位到细胞核中，当额外的脑提取物处理产生凋亡细胞死亡时。6-OHDA对金属硫蛋白- 1和-II敲除小鼠脑组织多巴胺能损伤的影响在MT-I、II敲除小鼠中显著加重，提示MT-I和-II对6-OHDA在黑质的多巴胺能神经毒性具有神经保护作用。