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Studies on apoptosis regulators substances of microbial origin aiming at neuroprotection

微生物来源的凋亡调节物质的神经保护研究

基本信息

批准号：
13660104
负责人：
SHIN-YA Kazuo
金额：
$ 2.18万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

The apoptosis to which the nerve cell death in central diseases, such as brain ischemia disease, Alzheimer's disease, and Parkinson's disease, advances by prolonged stress exposure except for an acute term is considered to be the cause of development of symptoms. If a nerve cells become senile, folding of the protein in an endoplasmic reticulum will become unusual, and, as a result, old junk proteins will be accumulated. It has been shown clearly by the latest research that this is the main causes of the long-term stress of a nerve cell. β-Amyloid peptide acts as nerve toxicity especially about Alzheimer's disease. The production of this peptide originates in misfolding of the amyloid precursor protein (APP) being caused by endoplasmic reticulum stress. Therefore, it is expected by the promotion of discovery of the molecular chaperone which performs a protein folding, especially the factor called GRP78 that these central disease can recover. Therefore, it is expected by the promotion o … More f discovery of the molecular chaperone which performs a proteinic folding, especially the factor called GRP78 that these central disease can recover. As a result of screening for the regulators of GRP78 expression, the new substance designated as versipelostatin was discovered as an inhibitor of molecular chaperone expression from the microbial secondary metabolites. Although development was furthered as a present anti-neoplasm agent in order that this substance might indicate a reverse action to be a central disease curative medicine, as a result of examining the effect over a nerve cell, it became clear that the same nerve cell death as the model of Alzheimer's disease was guided, and it became clear that this substance is a useful tool proving the onset of Alzheimer's disease and the relation of endoplasmic reticulum stress. The cause of stress is indued by the oxygen radical besides the above-mentioned endoplasmic reticulum stress over a long period of time. The typical thing is observed by the cell death of the substantia nigra which is the pathology view of Parkinson's disease. Then, as a result of screening for the substance which protects PC12 cell from the L-DOPA toxicity in which Parkinson's disease carries out and its promotion, the new substance halxazone was discovered. Although this substance showed cell protective activity by low concentration with an anti-oxidative activities, L-DOPA toxicity was not ameliorated by other antioxidants such as vitamin E. To reveal the action mechanism of halxazone against L-DOPA toxicity, the effects of antioxidants were examined using ESR. Only halxazone specifically scavenged the radical production from catechol oxidation.The still more detailed mechanism about the present book substance is due to be examined. Less

脑缺血性疾病、阿尔茨海默病、帕金森病等中枢性疾病中的神经细胞死亡通过除急性期以外的长期应激而进展的细胞凋亡被认为是症状发展的原因。如果神经细胞衰老，内质网中的蛋白质折叠将变得异常，结果，旧的垃圾蛋白质将积累。最新的研究已经清楚地表明，这是神经细胞长期受压的主要原因。β-淀粉样肽具有神经毒性作用，尤其是对阿尔茨海默病的神经毒性作用。这种肽的产生起源于内质网应激引起的淀粉样前体蛋白（APP）的错误折叠。因此，通过促进发现进行蛋白质折叠的分子伴侣，特别是被称为GRP 78的因子，可以预期这些中枢疾病可以恢复。因此，它是预期的推广o ...更多信息随着分子伴侣蛋白的发现，尤其是GRP 78的发现，这些中枢性疾病得以恢复。作为筛选GRP 78表达的调节剂的结果，发现了命名为versipelostatin的新物质作为微生物次级代谢产物的分子伴侣表达的抑制剂。尽管作为现有的抗肿瘤剂进一步开发，以便这种物质可以指示作为中枢疾病治疗药物的逆转作用，但作为检查对神经细胞的作用的结果，很明显，引导了与阿尔茨海默病模型相同的神经细胞死亡，很明显，这种物质是一种有用的工具，证明阿尔茨海默病的发病和内质网应激的关系。应激的原因除上述内质网应激外，长期存在的氧自由基也是引起应激的重要因素。典型的是观察到的黑质细胞死亡，这是帕金森病的病理观点。然后，作为筛选保护PC 12细胞免受帕金森病所进行的L-DOPA毒性的物质及其促进作用的结果，发现了新的物质哈沙宗。尽管这种物质在低浓度下表现出细胞保护活性并具有抗氧化活性，但维生素E等其他抗氧化剂并不能改善左旋多巴的毒性。为揭示哈沙宗抗左旋多巴毒性的作用机制，采用ESR技术研究了抗氧化剂的作用。只有Halxazone特异性地清除邻苯二酚氧化产生的自由基。关于本书物质的更详细的机制还有待研究。少