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
张正铎,吴虹,祁少俊,唐延金,高希宝
ZHANG Zhengduo, WU Hong, QI Shaojun, TANG Yanjin, GAO Xibao
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。
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