Up-regulation of glial cell line-derived neurotrophic factor by newly synthesized cyclopentenone derivatives : Studies on cellular mechanisms in vitro and effectiveness in vivo

新合成的环戊烯酮衍生物上调神经胶质细胞系源性神经营养因子：体外细胞机制和体内有效性研究

基本信息

批准号：
21500348
负责人：
HIRATA Yoko
金额：
$ 2.91万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

Newly synthesized(arylthio) cyclopentenone derivatives(GIF-0642, GIF-0643) suppressed manganese-induced apoptosis in PC12 cells by inhibiting caspase activation and cytochrome c release from mitochondria. GIF-0642 and GIF-0643 were also neuroprotective against oxidative stress-induced cell death in mouse hippocampal HT22 cells and C6 glioma cells. GIF-0642 and GIF-0643 bound to peroxisome proliferator-activated receptor-γ(PPARγ) and activated PPARγ-RXR heterodimers. Furthermore, these compounds induced gene expression of GDNF, BDNF and nerve growth factor(NGF) in C6 glioma cells. GIF-0642 and GIF-0643 stimulated phosphorylation of various signaling molecules in the MAP kinase pathway. We synthesized biotinylated(arylthio) cyclopentenones to study direct interaction between various signaling molecules in the MAP kinase pathway and chemical compounds using a pull-down assay. The results suggest that(arylthio) cyclopentenones directly bind to Raf molecule. On the other hand, intraperitoneal administration of GIF-0642 in mice failed to stimulate neurotrophic factors such as GDNF, BDNF, and NGF in the brain. Further study is required to determine the effects of(arylthio) cyclopentenones on the expression of neurotrophic factors in vivo. These include dosage of chemical compounds, solvents for dissolving chemical compounds to use, and the method of administration.

新合成的（芳硫基）环戊烯酮衍生物（GIF-0642、GIF-0643）通过抑制 caspase 激活和线粒体释放细胞色素 c 来抑制 PC12 细胞中诱导的锰细胞凋亡，GIF-0642 和 GIF-0643 也对氧化应激诱导的神经保护作用。小鼠海马 HT22 细胞和 C6 神经胶质瘤细胞的细胞死亡。 GIF-0642 和 GIF-0643 与过氧化物酶体增殖物激活受体-γ (PPARγ) 结合并激活 PPARγ-RXR 异二聚体。此外，这些化合物诱导 C6 GIF 细胞中 GDNF、BDNF 和神经生长因子 (NGF) 的基因表达。我们合成了 -0642 和 GIF-0643 刺激 MAP 激酶途径中各种信号分子的磷酸化。生物素化（芳硫基）环戊烯酮使用 Pull-down 测定法研究 MAP 激酶途径中的各种信号分子与化合物之间的直接相互作用，结果表明（芳硫基）环戊烯酮直接与 Raf 分子结合。 GIF-0642 在小鼠体内未能刺激大脑中的神经营养因子，如 GDNF、BDNF 和 NGF。 (芳硫基)环戊烯酮对体内神经营养因子表达的影响这些包括化合物的剂量、溶解化合物所使用的溶剂以及施用方法。