Faryadras Kimia, Golchoobian Ravieh, Iranzadeh Saeid, Roghani Mehrdad
School of Medicine, Shahed University, Tehran, Iran.
Department of Physiology, Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
Front Neurosci. 2025 May 23;19:1567236. doi: 10.3389/fnins.2025.1567236. eCollection 2025.
Learning and memory deficits are clinical characteristics of Alzheimer's disease (AD), often leading to diminished functionality. The neurotoxicant trimethyltin (TMT) is a valuable research tool for inducing cognitive impairment and hippocampal neurodegeneration and studying AD pathogenesis and treatment. Naringenin is a flavonoid with potential neuroprotective effects. This study sought to investigate the neuroprotective potential of naringenin against hippocampal neurodegeneration induced by TMT neurotoxicity and identify some underlying molecular mechanisms.
Neurodegeneration was induced through an 8 mg/kg intraperitoneal injection of TMT, followed by oral administration of naringenin (25 and 100 mg/kg) for 21 days. Behavioral assessments, including novel object discrimination (NOD), Y-maze, and passive avoidance tests, were carried out to evaluate cognitive functions. Biochemical assays for oxidative/nitrosative stress, mitochondrial membrane potential (MMP), inflammation, and acetylcholinesterase (AChE) enzyme activity, as well as AD pathology-specific markers, were conducted. To further validate the results, histological assessments of the CA1 hippocampal region using Nissl staining and immunohistochemical identification of 3-nitrotyrosine (3-NT) were performed.
Naringenin exhibited a dose-dependent inhibition of CA1 neuronal loss and reversed TMT-induced cognitive deficits. It markedly decreased hippocampal levels of malondialdehyde (MDA), nitrite, tumor necrosis factor-alpha (TNFα), and AChE activity while enhancing catalase and superoxide dismutase (SOD) activities, 3-nitrotyrosine (3-NT) immunoreactivity, and MMP. Furthermore, findings demonstrated that naringenin mitigated the TMT-induced elevation in hippocampal levels of AD-specific proteins, including phosphorylated tau (p-tau), amyloid-beta (Aβ), and presenilin 1. Naringenin may be postulated as a promising therapeutic candidate for AD and related neurodegenerative conditions by mitigating oxidative and nitrosative stress, maintaining mitochondrial integrity, decreasing inflammation, and modulating pathways of neurodegeneration.
学习和记忆缺陷是阿尔茨海默病（AD）的临床特征，常导致功能减退。神经毒素三甲基锡（TMT）是诱导认知障碍和海马神经变性以及研究AD发病机制和治疗方法的重要研究工具。柚皮素是一种具有潜在神经保护作用的黄酮类化合物。本研究旨在探讨柚皮素对TMT神经毒性诱导的海马神经变性的神经保护潜力，并确定一些潜在的分子机制。
通过腹腔注射8mg/kg的TMT诱导神经变性，随后口服柚皮素（25mg/kg和100mg/kg），持续21天。进行行为评估，包括新物体辨别（NOD）、Y迷宫和被动回避试验，以评估认知功能。进行氧化/亚硝化应激、线粒体膜电位（MMP）、炎症和乙酰胆碱酯酶（AChE）酶活性以及AD病理特异性标志物的生化检测。为了进一步验证结果，使用尼氏染色对海马CA1区进行组织学评估，并对3-硝基酪氨酸（3-NT）进行免疫组织化学鉴定。
柚皮素对CA1神经元丢失表现出剂量依赖性抑制作用，并逆转了TMT诱导的认知缺陷。它显著降低了海马中丙二醛（MDA）、亚硝酸盐、肿瘤坏死因子-α（TNFα）的水平和AChE活性，同时增强了过氧化氢酶和超氧化物歧化酶（SOD）活性、3-硝基酪氨酸（3-NT）免疫反应性和MMP。此外，研究结果表明，柚皮素减轻了TMT诱导的海马中AD特异性蛋白水平的升高，包括磷酸化tau（p-tau）、淀粉样β蛋白（Aβ）和早老素1。通过减轻氧化和亚硝化应激、维持线粒体完整性、减少炎症以及调节神经变性途径，柚皮素可能被认为是AD和相关神经退行性疾病的有前景的治疗候选物。
