Table5_Neuroprotective effects and possible mechanisms of berberine in animal models of Alzheimer’s disease: a systematic review and meta-analysis.docx

Background: Recently, multiple preclinical studies have reported the beneficial effect of berberine in the treatment of Alzheimer’s disease (AD). Nevertheless, the neuroprotective effects and possible mechanisms of berberine against AD are not universally recognized. This study aimed to conduct a systematic review and meta-analysis by integrating relevant animal studies to assess the neuroprotective effects and potential mechanisms of berberine on AD.
Methods: We systematically searched PubMed, Embase, Scopus and Web of Science databases that reported the effects of berberine on AD models up to 1 February 2023. The escape latency, times of crossing platform, time spent in the target quadrant and pro-oligomerized amyloid beta 42 (Aβ1-42) were included as primary outcomes. The secondary outcomes were the Tau-ps 204, Tau-ps 404, β-site of APP cleaving enzyme (BACE1), amyloid precursor protein (APP), acetylcholine esterase (AChE), tumor necrosis factor ⍺ (TNF-α), interleukin 1β (IL-1β), IL-6, nitric oxide (NO), glial fibrillary acidic protein (GFAP), malonaldehyde (MDA), glutathione S-transferase (GST), glutathione (GSH), glutathione peroxidase (GPx), Beclin-1 and neuronal apoptosis cells. This meta-analysis was conducted using RevMan 5.4 and STATA 15.1. The SYRCLE’s risk of bias tool was used to assess the methodological quality.
Results: Twenty-two studies and 453 animals were included in the analysis. The overall results showed that berberine significantly shortened the escape latency (p < 0.00001), increased times of crossing platform (p < 0.00001) and time spent in the target quadrant (p < 0.00001), decreased Aβ1-42 deposition (p < 0.00001), Tau-ps 202 (p < 0.00001) and Tau-ps 404 (p = 0.002), and improved BACE1, APP, AChE, Beclin-1, neuronal apoptosis cells, oxidative stress and inflammation levels.
Conclusion: Berberine may be a promising drug for the treatment of AD based on preclinical evidence (especially when the dose was 5–260 mg/kg). The potential mechanisms for these protective effects may be closely related to anti-neuroinflammation, anti-oxidative stress, modulation of autophagy, inhibition of neuronal apoptosis and protection of cholinergic system. However, these results may be limited by the quality of existing research. Larger and methodologically more rigorous preclinical research are needed to provide more convincing evidence.

背景：近期多项临床前研究均报道了小檗碱（berberine）在阿尔茨海默病（Alzheimer’s disease, AD）治疗中的获益作用。然而，小檗碱针对阿尔茨海默病的神经保护效应及其潜在作用机制尚未得到学界的广泛认可。本研究旨在通过整合相关动物实验开展系统评价与荟萃分析，以评估小檗碱对阿尔茨海默病的神经保护作用及潜在机制。
方法：我们系统检索了截至2023年2月1日发表于PubMed、Embase、Scopus及Web of Science数据库中、报道小檗碱对阿尔茨海默病模型作用的相关文献。本研究纳入的主要结局指标包括逃避潜伏期、平台穿越次数、目标象限停留时间以及前寡聚化淀粉样β蛋白42（pro-oligomerized amyloid beta 42, Aβ1-42）。次要结局指标则涵盖磷酸化Tau蛋白204位点（Tau-ps 204）、磷酸化Tau蛋白404位点（Tau-ps 404）、β位淀粉样前体蛋白裂解酶1（β-site of APP cleaving enzyme, BACE1）、淀粉样前体蛋白（amyloid precursor protein, APP）、乙酰胆碱酯酶（acetylcholine esterase, AChE）、肿瘤坏死因子α（tumor necrosis factor ⍺, TNF-α）、白细胞介素1β（interleukin 1β, IL-1β）、白细胞介素6（IL-6）、一氧化氮（nitric oxide, NO）、神经胶质原纤维酸性蛋白（glial fibrillary acidic protein, GFAP）、丙二醛（malonaldehyde, MDA）、谷胱甘肽S-转移酶（glutathione S-transferase, GST）、谷胱甘肽（glutathione, GSH）、谷胱甘肽过氧化物酶（glutathione peroxidase, GPx）、Beclin-1以及神经元凋亡细胞。本荟萃分析采用RevMan 5.4与STATA 15.1软件完成，并使用SYRCLE偏倚风险工具评估研究的方法学质量。
结果：本分析共纳入22项研究，涉及453只实验动物。整体分析结果显示，小檗碱可显著缩短实验动物的逃避潜伏期（p < 0.00001）、增加平台穿越次数（p < 0.00001）及目标象限停留时间（p < 0.00001），减少Aβ1-42沉积（p < 0.00001）、磷酸化Tau-ps 202（p < 0.00001）与磷酸化Tau-ps 404水平（p = 0.002），同时可改善BACE1、APP、AChE、Beclin-1、神经元凋亡细胞、氧化应激及炎症因子水平。
结论：基于现有临床前证据（尤其当给药剂量为5~260 mg/kg时），小檗碱有望成为治疗阿尔茨海默病的潜在药物。其发挥神经保护作用的潜在机制可能与抗神经炎症、抗氧化应激、调控自噬、抑制神经元凋亡以及保护胆碱能系统密切相关。然而，本研究结果仍受限于现有研究的质量，未来需开展更大样本量、方法学更严谨的临床前研究以提供更具说服力的证据。