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症状。

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 factor α (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 Aβ protein 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 Aβ in the hippocampus was significantly decreased (P < 0.01). The protein expression of anti-apoptotic factor Bcl-2 was significantly increased (P < 0.01), and the expression of pro-apoptotic proteins Bax and Caspase-3 was significantly decreased (P < 0.01). The protein expression of nuclear factor κB (NF-κB), p-p38, and inducible nitric oxide synthase (iNOS) was significantly decreased (P < 0.05, 0.01), and the protein expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) was significantly decreased (P < 0.01), while the protein expression of neprilysin (NEP) and insulin-degrading enzyme (IDE) was significantly increased (P < 0.01). Conclusion Cannabidiol can improve AD induced by D-gal/AlCl₃ in mice by reducing neuroinflammation, inhibiting neuronal apoptosis, and reducing Aβ protein deposition.

R285.5

吉林省科技发展计划项目（20220204028YY）