权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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激活和细胞色素c从线粒体释放来抑制锰诱导的PC 12细胞凋亡。GIF-0642和GIF-0643还对小鼠海马HT 22细胞和C6胶质瘤细胞中氧化应激诱导的细胞死亡具有神经保护作用。GIF-0642和GIF-0643结合过氧化物酶体增殖物激活受体-γ（PPARγ）和激活的PPARγ-RXR异二聚体。此外，这些化合物在C6胶质瘤细胞中诱导GDNF、BDNF和神经生长因子（NGF）的基因表达。GIF-0642和GIF-0643刺激MAP激酶途径中各种信号分子的磷酸化。我们合成了生物素化的（芳硫基）环戊烯酮，以研究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）环戊烯酮直接结合Raf分子。另一方面，将GIF-0642腹膜内给予小鼠不能刺激脑中的神经营养因子如GDNF、BDNF和NGF。需要进一步的研究，以确定（芳硫基）环戊烯酮对神经营养因子在体内的表达的影响。这些包括化合物的剂量、用于溶解要使用的化合物的溶剂以及给药方法。