大麻二酚对D-半乳糖/三氯化铝诱导的阿尔茨海默病模型小鼠的神经保护作用及机制  

Neuroprotective effect and mechanism of cannabidiol on D-galactose/aluminum chloride-induced Alzheimer's disease model mice

作　　者：李申晖 杨舸 高岩松 李盛钰[2] 赵雷 LI Shenhui;YANG Ge;GAO Yansong;LI Shengyu;ZHAO Lei(School of Pharmaceutical Sciences,Changchun University of Chinese Medicine,Changchun 130117,China;Institute of Agro-food Technology,Jilin Academy of Agricultural Sciences(Northeast Agricultural Research Center of China),Changchun 130033,China)

机构地区：[1]长春中医药大学药学院,吉林长春130117 [2]吉林省农业科学院(中国农业科技东北创新中心)农产品加工研究所,吉林长春130033

出　　处：《药物评价研究》2025年第3期618-626,共9页Drug Evaluation Research

基　　金：吉林省科技发展计划项目(20220204028YY)。

摘　　要：目的探究大麻二酚在阿尔茨海默症(AD)模型小鼠中的干预效果及其潜在的分子作用机制。方法使用D-半乳糖/三氯化铝(AlCl3)诱导建立AD小鼠模型,对照组不造模。将造模小鼠随机分为4组:模型组、多奈哌齐(5 mg∙kg−1)组和大麻二酚低、高剂量(100、200 mg∙kg−1)组,连续ig给药21 d,对照组和模型组ig等量CMC-Na溶液。进行跳台实验和爬杆实验;试剂盒法检测AD小鼠血清中肿瘤坏死因子α(TNF-α)、小鼠白细胞介素1β(IL-1β)、小鼠白细胞介素6(IL-6)、小鼠白细胞介素10(IL-10)的表达水平,以及小鼠海马中神经递质乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)水平;采用苏木精-伊红(HE)染色分析小鼠海马组织学变化;通过免疫荧光染色对小鼠海马体内β-淀粉样(Aβ)蛋白进行定量分析;采用Western blotting法检测海马组织神经炎症、神经凋亡相关信号蛋白表达的变化。结果与模型组比较,多奈哌齐组和大麻二酚组AD小鼠的跳台实验被动回避潜伏期显著延长,错误次数显著减少(P<0.05、0.01),爬杆实验AD小鼠的下降时间显著缩短(P<0.05、0.01);血清中促炎因子TNF-α、IL-1β、IL-6水平显著降低(P<0.01),抗炎因子IL-10的水平显著升高(P<0.01);AD小鼠脑组织内AChE和BChE的表达水平显著降低(P<0.01);海马组织病理改变显著改善,细胞结构正常,排列紧密,少量坏死;海马组织Aβ阳性率显著降低(P<0.01);海马体内抗凋亡因子Bcl-2的蛋白表达量显著升高(P<0.01),促凋亡蛋白Bax和Caspase-3的表达量显著降低(P<0.01);核因子κB(NF-κB)、p-p38和一氧化氮合酶(iNOS)的蛋白表达量显著降低(P<0.05、0.01),β-位淀粉样前体蛋白裂解酶1(BACE1)的蛋白表达量显著降低(P<0.01),脑啡肽酶(NEP)和胰岛素降解酶(IDE)的蛋白表达量显著增加(P<0.01)。结论大麻二酚能够通过降低神经炎症、抑制神经细胞凋亡、减低Aβ蛋白沉积等方式,改善由D-半乳糖/AlCl3诱导的小鼠AD症Objective To investigate the intervention effects and potential molecular mechanisms of cannabidiol in an Alzheimer's disease(AD)mouse model.Methods The AD mouse model was established by using D-galactose(D-gal)/aluminum chloride(AlCl3),while the control group was not modeled.The modeled mice were randomly divided into 4 groups:model group,donepezil(5 mg∙kg−1)group and low and high dose cannabidiol(100,200 mg∙kg−1)groups.The mice were ig administered for 21 d,and the control group and model group were ig administered with the same amount of CMC-Na solution.The step-down test and pole test were conducted.The expression levels of tumor necrosis factorα(TNF-α),interleukin 1β(IL-1β),interleukin 6(IL-6),and interleukin 10(IL-10)in the serum of AD mice and the levels of neurotransmitters acetylcholinesterase(AChE)and butyrylcholinesterase(BChE)in the hippocampus were detected by the kit method.The histological changes of the hippocampus were analyzed by hematoxylin-eosin(HE)staining.The Aβprotein in the hippocampus of mice was quantitatively analyzed by immunofluorescence staining.The changes in the expression of neuroinflammation and neuroapoptosis-related signal proteins in the hippocampus were detected by Western blotting.Results Compared with the model group,the passive avoidance latency in the step-down test and the number of errors in the donepezil group and the cannabidiol groups were significantly prolonged and reduced(P<0.05,0.01),respectively,and the descent time in the pole test was significantly shortened(P<0.05,0.01).The levels of pro-inflammatory factors TNF-α,IL-1β,and IL-6 in the serum were significantly decreased(P<0.01),and the level of anti-inflammatory factor IL-10 was significantly increased(P<0.01).The expression levels of AChE and BChE in the brain tissue of AD mice were significantly decreased(P<0.01).The pathological changes in the hippocampus were significantly improved,with normal cell structure and tight arrangement,and a small amount of necrosis.The positive rate of Aβin the

关 键 词：大麻二酚 阿尔茨海默病 神经炎症 神经细胞凋亡 Β-淀粉样蛋白 

分 类 号：R285.5[医药卫生—中药学]