Faryadras_2025_Front.Neurosci_19_1567236

INTRODUCTION: 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. METHODS: 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. RESULTS AND DISCUSSION: 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 (TNFalpha), 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 (Abeta), 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.