SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Gate No.1, Mithibai College Campus, Vaikunthlal Mehta Rd, Vile Parle West, Mumbai, Maharashtra 400056, India.
SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Gate No.1, Mithibai College Campus, Vaikunthlal Mehta Rd, Vile Parle West, Mumbai, Maharashtra 400056, India; Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
Behav Brain Res. 2025 Jan 5;476:115270. doi: 10.1016/j.bbr.2024.115270. Epub 2024 Sep 22.
Alzheimer's disease (AD), a chronic neurodegenerative disease, presents a substantial global health challenge. This study explored the potential therapeutic role of famotidine, a histamine (H2) receptor antagonist, as a glycogen synthase kinase-3β (GSK-3β) inhibitor in the context of AD induced by aluminium chloride (AlCl) in a rat model. The intricate relationship between GSK-3β dysregulation and AD pathogenesis, particularly in amyloid-β (Aβ) production, formed the basis for investigating famotidine's efficacy. Molecular modelling revealed famotidine's efficient binding to GSK-3β, suggesting inhibitory potential. In behavioural assessments, famotidine-treated groups exhibited dose-dependent improvements in Morris Water Maze, Novel Object Recognition, and Y-Maze tests, comparable to the standard Rivastigmine tartrate group. Biochemical analyses showed that famotidine inhibits acetylcholinesterase, decreases lipid peroxidation, increases antioxidant activity, and mitigates oxidative stress. Moreover, famotidine significantly lowered the levels of GSK-3β, IL-6, and Aβ(1-42). The neuroprotective effects of famotidine were further supported by histopathological analysis. This comprehensive investigation underscores famotidine's potential as a GSK-3β inhibitor, providing insights into its therapeutic impact on AD induced by AlCl. The study offers a promising avenue for repurposing famotidine due to its established safety profile and widespread availability, highlighting its potential in addressing the formidable challenge of AD.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，是一项全球性的重大健康挑战。本研究旨在探讨法莫替丁（一种组胺（H2）受体拮抗剂）作为氯化铝（AlCl）诱导的 AD 大鼠模型中糖原合酶激酶-3β（GSK-3β）抑制剂的潜在治疗作用。GSK-3β 失调与 AD 发病机制之间的复杂关系，特别是在淀粉样蛋白-β（Aβ）产生方面，为研究法莫替丁的疗效提供了依据。分子建模揭示了法莫替丁与 GSK-3β 的有效结合，提示其具有抑制潜力。在行为评估中，法莫替丁治疗组在 Morris 水迷宫、新物体识别和 Y 迷宫测试中表现出剂量依赖性改善，与标准的 Rivastigmine tartrate 组相当。生化分析表明，法莫替丁抑制乙酰胆碱酯酶，降低脂质过氧化，增加抗氧化活性，减轻氧化应激。此外，法莫替丁还显著降低了 GSK-3β、IL-6 和 Aβ（1-42）的水平。法莫替丁的神经保护作用还得到了组织病理学分析的支持。这项综合研究强调了法莫替丁作为 GSK-3β 抑制剂的潜力，为其在 AlCl 诱导的 AD 中的治疗作用提供了新的认识。由于法莫替丁具有良好的安全性和广泛的可用性，因此该研究为重新利用法莫替丁提供了一个有前途的途径，突出了其在应对 AD 这一艰巨挑战方面的潜力。
