石菖蒲活性成分对Aβ35825;导的神经元凋亡及ASK1-JNK信号转导通路的影响

项目名称： 石菖蒲活性成分对Aβ35825;导的神经元凋亡及ASK1-JNK信号转导通路的影响

项目编号： No.30873396

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 牛英才

作者单位： 齐齐哈尔医学院

项目金额： 33万元

中文摘要： 本研究观察了石菖蒲的活性成分β#32454;辛醚对Aβ35825;导的神经元凋亡及ASK1-JNK信号转道通路的影响。结果显示，β#32454;辛醚对Aβ-35诱导的PC12细胞凋亡具有抑制作用。（2）β#32454;辛醚抑制Aβ-35诱导的PC12细胞凋亡作用与JNK信号通路有关。可通过抑制JNK→#25233;制Bcl-xL和Bcl-w→#25233;制Cyt-C释放→#38477;低caspase-3激活→#25233;制凋亡。（3）β#32454;辛醚对Aβ42诱导的AD模型SH-SY5Y细胞具有明显的保护作用，Aβ42诱导 SH-SY5Y细胞凋亡的作用机制与ASK1/MKK7/JNK激酶级联反应和细胞线粒体信号通路相关。（4）β#32454;辛醚对Aβ42所致AD模型大鼠学习记忆障碍具有明显改善作用。（5）β#32454;辛醚对Aβ42双侧海马注射诱导的AD模型大鼠海马神经细胞凋亡有一定保护作用，其作用机理可能是通过抑制神经细胞中ASK-1、p-JNK、Bax、Caspase-3的表达和促进Bcl-2的表达来实现的。因此，我们的结果表明：β#32454;辛醚可能是防治老年性性痴呆的潜在药物。我们的研究成果在SCI期刊源期刊发表科研论文4篇。

中文关键词： 石菖蒲活性成分；JNK信号转导通道；老年性痴呆；Aβ65307;细胞凋亡

英文摘要： In this study, Our data show: (1) Significant induction of apoptosis in PC12 cells incubated with Aβeptide, and this effect was reduced by βsarone. Beta-asarone reduced Aβnduced JNK activation. In addition, βsarone attenuates Aβnduced down-regulation of Bcl-w and Bcl-xL in a JNK-dependent manner, and subsequent inhibition mitochondrial release of cytochrome c and activation of caspase-3. (2) The Aβ1-42) injection caused impairments in spatial reference memory in a Morris water maze task and apoptosis in hippocampus. Oral administration of βsarone for 28 d ameliorated Aβ1-42)-induced cognitive impairment and reversed the increase of apoptosis in the hippocampus. Aβnduced JNK results in phosphorylation, subsequent down-regulation of Bcl-2 and Bcl-w expression, and caspase-3 activation. Beta-asarone attenuate Aβ-42)-induced neuronal apoptosis in hippocampus by reversal down-regulation of Bcl-2, Bcl-w, caspase-3 activation, and JNK phosphorylation. (3) Intrahippocampal injections of Aβ1-42) caused apoptosis in rat hippocampus. Oral administration of βsarone reverse the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus tissue. βsarone afforded a beneficial inhibition on both mRNA and protein expression of Bad, Bax, and cleavage of caspases 9 in rat hippocampus following intrahippocampal injections of Aβ1-42).ASK1, p-MKK7, and p-c-jun were significantly decreased after βsarone treatment, implicating that the modulation of ASK1/c-JNK-mediated intracellular signaling cascades could be involved neuroprotection of βsarone against Aβoxicity. βsarone afforded protection against A?-induced toxicity through inhibiting apoptosis in SH-SY5Y cells. This result was also confirmed by the activities of caspase-9 and caspase-3 assay. P-ASK1, MKK7, p-JNK, Bax, Bad expression and cytochrome c release decreased after pretreatment with βsarone in SH-SY5Y cells exposed to AβThese effects of βsarone against Aβnsult were enhanced by ASK1 siRNA. Together, these findings indicate that βsarone might be a potentially therapeutic compound for Alzheimer's disease. We have finished 4 research papers.

英文关键词： Active Components from Acorus Tatarinowii Schott; JNK Signal Transduction Pathway; Alzheimer's disease; amyloid-βrotein; Apoptosis