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Research and Development of Neuroprotective Drugs Targeted for Glial Cells

胶质细胞靶向神经保护药物的研发

基本信息

批准号：
13557222
负责人：
KOYAMA Yutaka
金额：
$ 5.31万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557222/
关键词：
Glia cells Astrocyte GDNF Neurotrophic drugs BDNF neurotrophic factors 海馬グルタミン酸脳浮腫 Na Ca交換輸送

项目摘要

Effects of Endothelin Receptor Agonists on Neurotrophic Factor Production in cultured Astrocytes: Re-generation of nervous systems after injury is supported by neurotrophic substances produced by astrocytes. In this study, we examined effects of a receptor agonist of endothelin-1 (ET-1), which increased in damages brain, on neurotrophic factor production in astrocytes. ET-1 stimulated expressions of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in cultured astrocytes. Intracerebroventircular administration of an ET receptor agonist Into rat brain increases both mRNA and protein levels of GDNF in hippocampus. BDNF expression in caudate putamen and cerebrum also increased by the ET agonist. Cultured astrocytes had exon 3 and exon 4-containing BDNF transcripts, but not exon 1 and exon 2 transcripts. Treatment with ET-1 increased both exon 3 and exon 4-containing BDNF transcripts. Examinations on ET-induced astrocytic BDNF transcription showed that the exon 3 of DNF gene were induced by ERK and CREB-mediated mechanisms. The exon 4 BDNF gene was shown to be mediated by C/EBPβ-mediated mechanisms. These results suggest that ET receptors are possible target of neurotrophic drugs.Mechanisms of novel neurotrophic drugs: T-588, a navel drug showing nouroprotective actions, caused Erk activation in rat hippocampus. Also, we found FK960, which have cognitive enhancing actions in animal models, stimulated GDNF production in rat cultured astrocytes. These actions of novel neurotrophic drugs may underlie their phsrmacological actions.

内皮素受体激动剂对培养的星形胶质细胞中神经营养因子产生的影响：损伤后神经系统的再生得到星形胶质细胞产生的神经营养物质的支持。在这项研究中，我们研究了内皮素-1 (ET-1) 受体激动剂（ET-1）对星形胶质细胞中神经营养因子产生的影响，这种受体激动剂会增加大脑损伤。 ET-1 刺激培养的星形胶质细胞中胶质细胞源性神经营养因子 (GDNF) 和脑源性神经营养因子 (BDNF) 的表达。脑室内给予大鼠脑内 ET 受体激动剂可增加海马中 GDNF 的 mRNA 和蛋白质水平。 ET 激动剂也增加了尾壳核和大脑中 BDNF 的表达。培养的星形胶质细胞具有包含外显子 3 和外显子 4 的 BDNF 转录本，但没有外显子 1 和外显子 2 转录本。 ET-1 治疗增加了含有外显子 3 和外显子 4 的 BDNF 转录本。对ET诱导的星形胶质细胞BDNF转录的检测表明，DNF基因的外显子3是由ERK和CREB介导的机制诱导的。外显子 4 BDNF 基因被证明是由 C/EBPβ 介导的机制介导的。这些结果表明ET受体可能是神经营养药物的靶点。新型神经营养药物的作用机制：具有神经保护作用的脐药T-588引起大鼠海马Erk激活。此外，我们发现 FK960 在动物模型中具有认知增强作用，可刺激大鼠培养的星形胶质细胞中 GDNF 的产生。新型神经营养药物的这些作用可能是其药理学作用的基础。