生长分化因子15在LPS诱导的帕金森病模型中的保护作用及机制

Protective effect and mechanism of growth differentiation factor-15 in LPS-induced models of Parkinson’s disease

目的探究生长分化因子15(GDF15)在脂多糖(LPS)诱导的帕金森病神经炎症中的保护作用及其机制。方法筛选LPS作用于BV2细胞的合适时间,分为空白组、3 h组、6 h组、12 h组和24 h组;筛选LPS作用于BV2细胞的合适浓度,分为空白组、0.5 mg/mL组、1 mg/mL组和2 mg/mL组;探究外源性GDF15作用时,BV2细胞分为空白组、LPS组和LPS+GDF15组;实验动物分为野生小鼠对照组(WT组)、野生小鼠模型组(WT+LPS组)和GDF15敲除小鼠模型组(KO+LPS组)。采用Western blotting法检测信号转导和转录激活因子3(STAT3)/核转录因子κB(NF-κB)/细胞外信号调节激酶(ERK)蛋白表达水平,采用qPCR法检测肿瘤坏死因子(TNF-α)、白细胞介素(IL-1β)、诱导型一氧化氮合酶(iNOS)、环氧合酶-2(COX-2)的表达水平,使用显微镜观察BV2小胶质细胞形态变化。结果外源性GDF15通过抑制STAT3/NF-κB/ERK信号通路,可降低TNF-α、IL-1β、iNOS、COX-2等炎症分子的表达,GDF15敲除小鼠模型组黑质、纹状体的炎症反应增强,TNF-α、IL-1β、iNOS、COX-2等炎症分子的表达升高。结论GDF15在帕金森病的炎症模型中可以通过STAT3/NF-κB/ERK信号通路降低炎症因子的表达,GDF15通过抑制炎症因子的分泌进而在帕金森病的进展中发挥保护作用,为帕金森病的防治提供新的靶点。

Objective To investigate the protective effect and mechanism of growth differentiation factor 15(GDF15)in lipopolysaccharide(LPS)induced neuroinflammation associated with Parkinson’s disease.Methods To explore the optimum time of LPS,BV2 cells were divided into blank,3 h,6 h,12 h and 24 h groups;to explore the optimum concentration of LPS,BV2 cells were divided into blank,0.5,1 and 2 mg/mL groups;to explore the effect of GDF15,BV2 cells were divided into blank,LPS and LPS+GDF15 groups.The mice were divided into WT,WT+LPS and KO-LPS group.The protein expressions of STAT3,NF-κB and ERK were detected with Western blotting.The mRNA expressions of TNF-α,IL-1β,iNOS and COX-2 were detected with qPCR.The effect of GDF15 on the morphology of LPS-induced BV2 cells was observed with a microscope.Results GDF-15 suppressed the expressions of TNF-α,IL-1β,iNOS and COX-2 by inhibiting the STAT3/NF-κB/ERK signaling pathway.In the substantia nigra and striatum of the GDF15 knockout mice,the expressions of TNF-α,IL-1β,iNOS and COX-2 increased.Conclusion GDF15 can attenuate the expressions of TNF-α,IL-1β,iNOS and COX-2 through STAT3/NF-κB/ERK signaling pathway,indicating it is a protective factor in the progression of Parkinson’s disease.It can provide a new therapeutic target for the prevention and treatment of this disease.