目的 了解杨梅酮对D-半乳糖诱导的衰老期小鼠认知障碍的影响及可能机制。方法 36只5 w龄C57BL/6J雄性小鼠随机分为三组：对照组（Con）,D-半乳糖诱导的衰老模型组（D-gala,150 mg/kg）,杨梅酮干预组（D-gala+Myr,100 mg/kg杨梅酮）。以D-半乳糖诱发衰老,并以杨梅酮同步进行干预。8 w后,用Morris水迷宫评价小鼠的学习记忆和空间探索能力,并进行海马组织病理学形态观察,测定海马NLRP3、Cleaved Caspase-1的表达及下游IL-1β、IL-18等炎症因子的水平,靶向NLRP3的相关miRNAs的表达水平。结果 杨梅酮显著缩短D-半乳糖所致的小鼠逃避潜伏期延长,增加小鼠在目标象限的停留时间,伴随海马CA1、CA3和DG区神经元排列整齐,数量增加。同时,杨梅酮延缓D-半乳糖诱导的海马BDNF水平下降,显著上调miR-7、miR-138-5p和miR-30e的表达,抑制靶基因NLRP3及Cleaved caspase-1 (p10)的蛋白和基因表达,降低IL-1β、IL-18和TNF-α的水平。结论 杨梅酮调节靶向至NLRP3的miRs的表达,抑制海马NLRP3/Caspase-1信号通路的激活和炎症反应,改善认知障碍。
Abstract
Objective To explore the effects of myricetin on cognitive impairment and potential mechanism in D-galactose-induced aging mice. Methods Thirty-six male C57BL/6J mice aged 5 weeks were randomly divided into three groups: control (Con) group, D-galactose-induced aging group (D-gala, 150 mg/kg), myricetin intervention on D-galactose-induced aging group (D-gala+Myr, 100 mg/kg myricetin). Aging was induced by D-galactose and myricetin was simultaneously used as the intervention. Eight weeks later, Morris water maze test was conducted to assess the learning and memory ability, which was followed by whole brain histology analysis, measurement of hippocampal NLRP3 and Caspase-1 expressions, as well as the inflammatory markers (IL-1β and IL-18 levels). Additionally, the expression of microRNAs that targeted on NLRP3 was also determined. Results Myricetin significantly decreased escape latency which was increased by D-galactose, and increased the time spent in the target quadrant. Myricetin treatment also resulted in well-arranged and increasing number of neurons in hippocampal CA1, CA3 and DG regions. Myricetin remarkably reversed the hippocampal BDNF decline induced by D-galactose, significantly up-regulated miR-7, miR-138-5p and miR-30e expressions and inhibited the expression of their target gene NLRP3 and subsequent cleaved caspase-1 (p10), decreased IL-1β, IL-18 and TNF-α levels. Conclusion Myricetin can regulate the expressions of miRs that targets on NLRP3, inhibit the activation of NLRP3/ Caspase-1 signaling pathway and hippocampal inflammation, and ultimately improve cognitive impairment.
关键词
认知障碍 /
杨梅酮 /
NLRP3 /
炎症反应 /
衰老
Key words
cognitive impairment /
myricetin /
nlrp3 /
inflammation /
aging
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基金
中国博士后基金（No.2017M620191）
