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山东大学学报 (医学版) ›› 2022, Vol. 60 ›› Issue (3): 13-23.doi: 10.6040/j.issn.1671-7554.0.2021.0947

• • 上一篇    

口服5-甲基四氢叶酸对大鼠阿尔茨海默病的预防作用

张正铎,吴虹,祁少俊,唐延金,高希宝   

  • 发布日期:2022-03-09
  • 通讯作者: 高希宝. E-mail:chem@sdu.edu.cn
  • 基金资助:
    山东省重点研发计划(公益类科技攻关:2019GSF107002)

Preventive effects of oral 5-methyltetrahydrofolate on Alzheimers disease in rats

ZHANG Zhengduo, WU Hong, QI Shaojun, TANG Yanjin, GAO Xibao   

  1. Department of Physical and Chemical Inspection, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
  • Published:2022-03-09

摘要: 目的 研究5-甲基四氢叶酸(5-MTHF)对D-半乳糖(D-gal)和氯化铝(AlCl3)诱导的阿尔茨海默病(AD)大鼠的学习和记忆功能的预防作用,以期为AD的预防提供新的解决方案。 方法 将40只雄性Wistar大鼠根据体质量的单因素方差分析结果分为对照组、模型组、AD+L-5-MTHF预防组和AD+H-5-MTHF预防组,每组10只。模型组每天给予腹腔注射60 mg/kg BW D-gal和10 mg/kg BW AlCl3,并用与其他各组等容量匹配的生理盐水灌胃6周。2个预防组每天在腹腔注射60 mg/kg BW D-gal和10 mg/kg BW AlCl3同时用1 mg/kg BW(低剂量组)或5 mg/kg BW 5-MTHF(高剂量组)灌胃 6周。采用Morris水迷宫来评价大鼠学习和记忆功能,用β-淀粉样蛋白1-42(Aβ1-42)和磷酸化Tau 蛋白(p-Tau)含量、解整合素样金属蛋白酶10(ADAM10)和β位淀粉样前体蛋白裂解酶1(BACE1)mRNA表达来评价AD大鼠淀粉样前体蛋白(APP)加工过程。采用乙酰胆碱酯酶(AChE)活力来评价胆碱能功能,用超氧化物歧化酶(SOD)和丙二醛(MDA)来评价氧化应激,用细胞因子来评价内皮细胞功能。 结果 水迷宫结果显示各组的潜伏期均随训练时间的增加而逐渐减少(F时间=67.37, P<0.001; F处理组=6.36, P=0.001)。而且,时间因素与分组因素在潜伏期上存在交互作用(F处理组x时间=2.72, P=0.007)。与对照组相比,模型组大鼠的潜伏期、脑中Aβ1-42和p-Tau含量、血清AChE和一氧化氮合酶(NOS)活力、肿瘤坏死因子-α(TNF-α)、内皮素-1(ET-1)、MDA和白介素-6(IL-6)的含量和海马BACE1 mRNA表达升高(P<0.05),血清SOD活力和海马ADAM10 mRNA表达降低(P<0.05),提示AD造模成功。与模型组相比,AD+L-5-MTHF组大鼠穿越平台次数、目标象限停留时间、血清SOD活力和海马ADAM10 mRNA表达上升(P<0.05)、潜伏期、血清IL-6含量及海马BACE1 mRNA表达下降(P<0.05);AD+H-5-MTHF组大鼠的潜伏期及血清一氧化氮(NO)和TNF-α含量下降(P<0.05)。而且,5-MTHF预防组间ADAM10 mRNA表达存在剂量依赖性(P=0.016)。 结论 5-MTHF可以改善D-gal和AlCl3诱导的AD大鼠学习和记忆损伤,其潜在机制可能是通过调节APP加工、内皮细胞分泌和抑制氧化应激来实现的。

关键词: 5-甲基四氢叶酸, D-半乳糖, 阿尔茨海默病, 氯化铝, 大鼠

Abstract: Objective To explore the preventive effects of 5-methyltetrahydrofolate(5-MTHF)on D-galactose(D-gal)and aluminum chloride(AlCl3)induced cognitive decline in Alzheimers disease(AD)rats. Methods A total of 40 male Wistar rats were divided into control group, model group, low-5-MTHF group and high-5-MTHF group according to body weight, with 10 rats in each group. The model group was given intraperitoneal injection of 60 mg/kg BWD-gal and 10 mg/kg BW AlCl3, and intragastric administration of physiological saline for 6 weeks. The low and high 5-MTHF groups were given intraperitoneal injection of 60 mg/kg BW D-gal and 10 mg/kg BW AlCl3, and intragastric administration of 1 mg/kg BW(low-5-MTHF group)or 5 mg/kg BW(high-5-MTHF group)for 6 weeks. The learning and memory function of rats were evaluated with Morris water maze. The processing of amyloid precursor protein(APP)was evaluated with the content of β-amyloid protein 1-42(Aβ1-42)and phosphorylated Tau protein(p-Tau), mRNA expression of disintegrin and metallopeptidase domain 10(ADAM10), and β-site amyloid precursor protein cleaving enzyme 1(BACE1). The cholinergic function was determined with the activity of acetylcholinesterase(AChE), oxidative stress was determined with superoxide dismutase(SOD)and malondialdehyde(MDA), and endothelial cell function was determined with cytokines. Results The water maze results showed that the escape latency of each group gradually decreased with the increase of training time(Fday=67.37, P<0.001; Fgroup=6.36, P=0.001). Moreover, there was an interaction between group and day factors in escape latency(Fday x group=2.72, P=0.007). Compared with the control group, the model group had longer escape latency, increased contents of Aβ1-42 and p-Tau in the brain, higher activites of serum AChE and nitric oxide synthase(NOS), higher levels of tumor necrosis factor-α(TNF-α), endothelin-1(ET-1), MDA and interleukin-6(IL-6)and higher BACE1 mRNA expression in the hippocampus(P<0.05), but decreased activity of serum SOD and lower ADAM10 mRNA expression in the hippocampus(P<0.05), suggesting the success of AD modeling. Compared with the model group, the low-5-MTHF group had larger numbers of crossing the platform, longer time spent in the target quadrant, higher activity of serum SOD and higher ADAM10 mRNA expression in the hippocampus(P<0.05), but shorter escape latency, lower content of serum IL-6 and reduced BACE1 mRNA expression(P<0.05). Compared with the model group, the high-5-MTHF group had shorter escape latency, lower content of Aβ1-42 in the brain, lower concentrations of serum nitric oxide(NO)and TNF-α(P<0.05). Moreover, the mRNA expression of ADAM10 between the 5-MTHF groups were dose-dependent(P=0.016). Conclusion 5-MTHF can prevent D-gal and AlCl3 induced cognitive decline in AD rats. The underlying mechanism may be achieved via regulating APP processing and endothelial cell secretion and repressing oxidative stress.

Key words: 5-methyltetrahydrofolate, D-galactose, Alzheimers disease, Aluminum chloride, Rat

中图分类号: 

  • R151
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