Yang Yishu, Wang Lili, Wu Yan, Su Dongmei, Wang Ning, Wang Jiedong, Shi Cuige, Lv Liping, Zhang Shucheng
Department of Neurology in Medical Healthcare Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
National Research Institute of Family Planning, Beijing, China.
Brain Res. 2016 Sep 1;1646:304-314. doi: 10.1016/j.brainres.2016.06.017. Epub 2016 Jun 15.
Neuroinflammation plays an important role in vascular dementia(VD). Our previous work showed that mammalian Ste20-like kinase 1 (MST1) and the gene for a downstream transcription factor, FOXO3, play major roles in lipopolysaccharide (LPS)-induced apoptosis in hippocampal neurons. The neurotoxic effects of LPS are derived from its ability to cause an inflammatory response. We also previously showed that Tanshinol (TSL) provides neuro-protection in a rat model of VD. The present study further explores the effects of TSL on the neuroinflammatory aspects of VD and investigates whether TSL affects the MST1-FOXO3signaling pathway. VD was induced in rats using transient bilateral coronary artery occlusion. Interleukin(IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels were measured using enzyme-linked immunoabsorbent assay kits. Cell apoptosis was assessed by Hoechst 33342 staining. Protein and mRNA levels were evaluated by western blotting and quantitative polymerase chain reaction, respectively. TSL improved working memory and significantly inhibited plasma and hippocampal protein levels of IL-1β, IL-6, and TNF-α in a rat model of VD. LPS induced apoptosis in hippocampal neurons and increasedMST1 and p-FOXO3 protein expression, whereas MST1 siRNA transfection almost completely reversed LPS-induced neuronal apoptosis, indicating that LPS-induced cytotoxicity in hippocampal neurons is associated with MST1. TSL protected against LPS-induced cell apoptosis and suppressed IL-1β, IL-6, and TNF-α mRNA and protein expression as well as MST1 and p-FOXO3 protein expression in neurons. The present study provided novel mechanisms by which TSL exerts its neuroprotective activity and indicates that TSL may be a potential neuro-protective agent in VD.
神经炎症在血管性痴呆（VD）中起重要作用。我们之前的研究表明，哺乳动物Ste20样激酶1（MST1）和下游转录因子FOXO3基因在脂多糖（LPS）诱导的海马神经元凋亡中起主要作用。LPS的神经毒性作用源于其引发炎症反应的能力。我们之前还表明，丹参素（TSL）在VD大鼠模型中具有神经保护作用。本研究进一步探讨TSL对VD神经炎症方面的影响，并研究TSL是否影响MST1-FOXO3信号通路。采用短暂双侧冠状动脉闭塞法诱导大鼠发生VD。使用酶联免疫吸附测定试剂盒测量白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNF）-α水平。通过Hoechst 33342染色评估细胞凋亡。分别通过蛋白质印迹法和定量聚合酶链反应评估蛋白质和mRNA水平。TSL改善了工作记忆，并显著抑制了VD大鼠模型中血浆和海马中IL-1β、IL-6和TNF-α的蛋白质水平。LPS诱导海马神经元凋亡并增加MST1和p-FOXO3蛋白表达，而MST1小干扰RNA转染几乎完全逆转了LPS诱导的神经元凋亡，表明LPS诱导的海马神经元细胞毒性与MST1有关。TSL可保护神经元免受LPS诱导的细胞凋亡，并抑制神经元中IL-1β、IL-6和TNF-α的mRNA和蛋白质表达以及MST1和p-FOXO3蛋白表达。本研究提供了TSL发挥其神经保护活性的新机制，并表明TSL可能是VD中一种潜在的神经保护剂。
