目的 探究大麻二酚在阿爾茨海默癥（AD）模型小鼠中的干預效果及其潛在的分子作用機制。方法 使用D-半乳糖/三氯化鋁（AlCl₃）誘導建立AD小鼠模型，對照組不造模。將造模小鼠隨機分為4組：模型組、多奈哌齊（5 mg∙kg⁻¹）組和大麻二酚低、高劑量（100、200 mg∙kg⁻¹）組，連續(xù)ig給藥21 d，對照組和模型組ig等量CMC-Na溶液。進行跳臺實驗和爬桿實驗；試劑盒法檢測AD小鼠血清中腫瘤壞死因子α（TNF-α）、小鼠白細胞介素1β（IL-1β）、小鼠白細胞介素6（IL-6）、小鼠白細胞介素10（IL-10）的表達水平，以及小鼠海馬中神經遞質乙酰膽堿酯酶（AChE）和丁酰膽堿酯酶（BChE）水平；采用蘇木精-伊紅（HE）染色分析小鼠海馬組織學變化；通過免疫熒光染色對小鼠海馬體內β-淀粉樣（Aβ）蛋白進行定量分析；采用Western blotting法檢測海馬組織神經炎癥、神經凋亡相關信號蛋白表達的變化。結果 與模型組比較，多奈哌齊組和大麻二酚組AD小鼠的跳臺實驗被動回避潛伏期顯著延長，錯誤次數顯著減少（P＜0.05、0.01），爬桿實驗AD小鼠的下降時間顯著縮短（P＜0.05、0.01）；血清中促炎因子TNF-α、IL-1β、IL-6水平顯著降低（P＜0.01），抗炎因子IL-10的水平顯著升高（P＜0.01）；AD小鼠腦組織內AChE和BChE的表達水平顯著降低（P＜0.01）；海馬組織病理改變顯著改善，細胞結構正常，排列緊密，少量壞死；海馬組織Aβ陽性率顯著降低（P＜0.01）；海馬體內抗凋亡因子Bcl-2的蛋白表達量顯著升高（P＜0.01），促凋亡蛋白Bax和Caspase-3的表達量顯著降低（P＜0.01）；核因子κB（NF-κB）、p-p38和一氧化氮合酶（iNOS）的蛋白表達量顯著降低（P＜0.05、0.01），β-位淀粉樣前體蛋白裂解酶1（BACE1）的蛋白表達量顯著降低（P＜0.01），腦啡肽酶（NEP）和胰島素降解酶（IDE）的蛋白表達量顯著增加（P＜0.01）。結論 大麻二酚能夠通過降低神經炎癥、抑制神經細胞凋亡、減低Aβ蛋白沉積等方式，改善由D-半乳糖/AlCl₃誘導的小鼠AD癥狀。

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

吉林省科技發(fā)展計劃項目（20220204028YY）