番茄红素通过激活FGF21信号通路减轻神经炎症和氧化应激改善D-半乳糖诱导的小鼠学习记忆能力下降的研究

SUPPLEMENTATION OF LYCOPENE ATTENUATES D-GALACTOSE-INDUCED COGNITIVE IMPAIRMENTS BY ALLEVIATING NEUROINFLAMMATION AND OXIDATIVE STRESS VIA FGF21 SIGNALING PATHWAY

目的 探究番茄红素是否可以改善D-半乳糖诱导的衰老模型小鼠学习记忆功能损伤及其具体分子机制。方法 45只雌性CD-1小鼠(2月龄)适应性喂养1w后,随机分为3组:对照组(control):腹腔注射生理盐水+标准饲料;D-半乳糖组(D-gal):腹腔注射150mg/(kg·d)D-半乳糖+标准饲料;番茄红素干预组(D-gal+LYC):腹腔注射150mg/(kg·d)D-半乳糖+番茄红素饲料(0.03%番茄红素,均匀混在标准饲料中),共8w。利用T迷宫检测各组小鼠的空间学习记忆能力;采用H&E染色、Westernblots以及免疫荧光分析番茄红素对D-半乳糖处理小鼠海马组织神经元形态、脑部神经营养因子以及突触功能蛋白PSD-95表达的影响。通过IBA-1免疫组化及Western blots检测小鼠脑部小胶质细胞激活、促炎因子TNFα、抗氧化物酶HO-1及NQO-1表达情况,分析番茄红素对D-半乳糖诱导的小鼠脑部神经炎症及氧化应激的改善作用。通过免疫组化以及Western blots方法分析番茄红素对小鼠脑部FGF21蛋白表达的影响,以探究FGF21是否对神经起保护作用。结果 T迷宫结果表明,番茄红素可以减轻D-半乳糖诱导的小鼠认知损伤,番茄红素减少了海马组织中核固缩及坏死的神经元细胞数量,促进了神经营养因子NT3/NGF以及突触功能蛋白PSD-95表达,减轻了D-半乳糖诱导的突触功能损伤。番茄红素通过增加抗氧化物酶HO-1、NQO-1表达,减轻了小鼠脑部氧化应激;通过抑制小胶质细胞过度激活以及下调脑部促炎因子TNFα表达,减轻了神经炎症。更重要的,番茄红素也促进了小鼠脑部FGF21的蛋白表达。结论 番茄红素可以通过减轻突触功能损伤,促进FGF21表达,改善脑部氧化应激以及神经炎症,减轻D-半乳糖诱导的小鼠认知功能损伤。

Objective To investigate the effects of lycopene(LYC) on D-galactose(D-gal) induced cognitive defects and the underlying mechanisms.Methods After 1 week acclimation period,forty-five female CD-1 mice(two-month-old)were randomly divided into 3 groups:control group receiving 0.9% physiological saline(intraperitoneally injected,i.p.) plus basal chow diet;D-gal group injected with 150 mg/(kg·d) D-gal(i.p.) plus basal chow diet;D-gal plus LYC group injected with 150 mg/(kg·d) D-gal(i.p.) plus 0.03% LYC(w/w,mixed with standard diet) for consecutive 8 weeks.Then,T-maze was used to assess the effects of LYC on spatial behaviors.H&E staining,Western blots and immunofluorescent staining were performed to detect the protein expressions of neurotrophic factors and synaptosomal associated protein PSD-95 and D-gal-induced pathological changes of neurons in hippocampal tissue.We detected the effect of LYC on D-gal-induced neuroinflammation and oxidative stress by IBA-1 immunohistochemical staining and the protein expressions of proinflammatory factor TNFα and antioxidant enzymes HO-1 and NQO-1 in mouse brains were also measured.Moreover,we investigated the improved effect of LYC on FGF21 to explore whether FGF21 was involved in the protective function of LYC on cognitive function.Results The behavioral tests indicated that LYC alleviated D-gal-induced cognitive impairments.LYC decreased the numbers of nuclear pyknosis and damaged neurons in the cortex of hippocampus and ameliorated synaptic dysfunction by increasing the expressions of neurotrophic factor NT3/NGF and synaptic protein PSD-95.LYC reduced oxidative stress and neuroinflammation by increasing the protein expressions of antioxidant enzymes HO-1 and NQO-1,inhibiting the activation of microglial cells and down-regulating the level of inflammatory cytokines TNFα in brains.More importantly,LYC also increased the protein expression of FGF21 in brains.Conclusion LYC suppresses D-gal-triggered cognitive defects by alleviating synaptic dysfunction,elevating the expression of FGF21 and attenuating oxidative stress,neuroinflammation in mouse brains.