文章基本信息

标题：Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury via Activation of the MAPK Pathway but Not of HSF1
本地全文：下载
作者：Jie Yu ; Zhuyun Jiang ; Ling Ning 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2015
卷号：38
期号：10
页码：1564-1572
DOI：10.1248/bpb.b15-00352
出版社：The Pharmaceutical Society of Japan
摘要：Heat-shock protein 70 (HSP70) is known to function as a protective molecular chaperone that is massively induced in response to misfolded proteins following cerebral ischemia. The objective of this study was to characterize HSP70 induction by Z-ligustilide and explore its potential role in protection against cerebral ischemia–reperfusion injury. Our results demonstrated that the intranasal administration of Z-ligustilide reduced infarct volume and improved neurological function in a rat stroke model. Meanwhile, Z-ligustilide enhanced the cell viability of PC12 cells insulted by oxygen–glucose deprivation-reoxygenation (OGD-Reoxy) and decreased apoptotic and necrotic cell death. Importantly, Z-ligustilide induced HSP70 expression both in vitro and in vivo . Although heat-shock factor 1 (HSF1) nuclear translocation was promoted by Z-ligustilide, HSP70-based heat-shock element (HSE)-binding luciferase activity was not activated, and HSP70 expression responsive to Z-ligustilide was not attenuated by HSE decoy oligonucleotides. However, Z-ligustilide significantly activated the phosphorylation of mitogen-activated protein kinases (MAPKs). Further inhibition of MAPK activity by specific inhibitors attenuated HSP70 induction by Z-ligustilide. Meanwhile, downregulation of HSP70 using KNK437, an HSP70 synthesis inhibitor, or small hairpin RNA (shRNA) significantly attenuated the protection of Z-ligustilide against OGD-Reoxy-induced injury. Moreover, the application of specific inhibitors of MAPKs also achieved similar results. Finally, Z-ligustilide alleviated the accumulation of ubiquitinated proteins induced by OGD-Reoxy, which was inhibited by HSP70-shRNA. Taken together, our results demonstrated that Z-ligustilide may induce protective HSP70 expression via the activation of the MAPK pathway, but not canonical HSF1 transcription. HSP70 plays a key role in the protection of Z-ligustilide against OGD-Reoxy-induced injury.