Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,1 Xian Nong Tan Street, Beijing 100050, PR China.
Brain Res. 2011 Apr 6;1383:99-107. doi: 10.1016/j.brainres.2011.01.093. Epub 2011 Feb 2.
Heat shock proteins (HSPs) play an essential role in various neurodegenerative diseases. Manipulation of upregulation of HSPs in cells has been demonstrated to provide a therapeutic strategy to counteract the misfolding and aggregation of proteins that resulted in neurodegenerative disease. Our previous studies have shown that FLZ, a synthetic novel derivative of squamosamide from a Chinese herb, had potent neuroprotective effect against several experimental Parkinson's disease (PD) models. However, the mechanism of its neuroprotective effect is still not clarified. The present study demonstrated that FLZ induced HSP27 and HSP70 proteins and mRNA expression in a time- and dose-dependent manner in SH-SY5Y cells. Further studies showed that FLZ treatment stimulated the activation of heat shock factor 1 (HSF1) and its regulatory kinase Akt. Inactivation of Akt pathway by the PI3K inhibitor LY294002 blocked the expression of HSP27 and HSP70 induced by FLZ. Moreover, the inducing effects of FLZ on HSP27, HSP70, and HSF1 were all blocked by quercetin, an inhibitor of HSP biosynthesis. The cytoprotective effect of HSP27/HSP70 induced by FLZ against MPP(+) was assessed in SH-SY5Y cells. The pretreatment of FLZ significantly induced the accumulations of HSP27/HSP70 and suppressed the apoptosis caused by MPP(+) in SH-SY5Y cells. However, the protective effects of FLZ against MPP(+) were significantly blocked by quercetin, which indicated that the cytoprotective action of FLZ against MPP(+)-induced apoptosis is at least partially mediated by its induction of HSP27/HSP70. These results provide new evidence for elucidating the mechanism of the neuroprotective effect of FLZ against PD.
热休克蛋白（HSPs）在各种神经退行性疾病中发挥着重要作用。研究表明，上调细胞内 HSPs 的表达可以提供一种治疗策略，以对抗导致神经退行性疾病的蛋白质错误折叠和聚集。我们之前的研究表明，FLZ，一种来自中药的新型 squamosamide 合成衍生物，对几种实验性帕金森病（PD）模型具有强大的神经保护作用。然而，其神经保护作用的机制尚不清楚。本研究表明，FLZ 以时间和剂量依赖的方式诱导 SH-SY5Y 细胞中 HSP27 和 HSP70 蛋白和 mRNA 的表达。进一步的研究表明，FLZ 处理刺激热休克因子 1（HSF1）及其调节激酶 Akt 的激活。PI3K 抑制剂 LY294002 使 Akt 通路失活，阻断了 FLZ 诱导的 HSP27 和 HSP70 的表达。此外，FLZ 对 HSP27、HSP70 和 HSF1 的诱导作用均被 HSP 生物合成抑制剂槲皮素阻断。FLZ 诱导的 HSP27/HSP70 对 MPP(+)的细胞保护作用在 SH-SY5Y 细胞中进行了评估。FLZ 的预处理显著诱导了 HSP27/HSP70 的积累，并抑制了 MPP(+)在 SH-SY5Y 细胞中引起的凋亡。然而，FLZ 对 MPP(+)的保护作用被槲皮素显著阻断，这表明 FLZ 对 MPP(+)-诱导的凋亡的保护作用至少部分是通过其诱导 HSP27/HSP70 介导的。这些结果为阐明 FLZ 对 PD 的神经保护作用机制提供了新的证据。
