Chronic stress, such as chronic unpredictable mild stress (CUMS), induces hippocampal oxidative stress, inflammation, and neurochemical imbalances, resulting in cognitive and synaptic deficits. However, the role of naringin, a citrus bioflavonoid with antioxidant and neurotrophic properties in reversing hippocampal oxidative–inflammatory effects in CUMS remains largely unexplored. This study uniquely elucidates the neurocognitive and synaptic mechanisms through which naringin restores hippocampal integrity, emphasizing its dual antioxidant and neurogenic actions against CUMS-induced cognitive dysfunction. Adult male mice were divided into six groups (n = 9/group): control, CUMS, naringin (2.5, 5, 10 mg/kg), and fluoxetine (10 mg/kg). All mice except the control group were exposed to CUMS daily for 21 days. After 21 days of treatment post-CUMS exposure, behavioral assessments, biochemical assays, immunohistochemical assay for neuroplasticity-related proteins, and histological analyses were conducted. Naringin significantly improved memory performance in the Y-Maze and NORT, as evidenced by increased % alternation and discrimination index. Naringin significantly reduced nitrite and acetylcholinesterase enzyme activity while attenuating the depletion of reduced glutathione, superoxide dismutase and catalase activities in the brains of CUMS mice. CUMS exposure increased proinflammatory cytokines (TNF-α and IL1-β), which were attenuated by naringin. Likewise, hippocampal neurotransmitters, including serotonin, dopamine and noradrenaline, were restored by naringin relative to CUMS group. Naringin upregulated neurotrophic (BDNF), neuronal (NeuN), and proliferative (Ki-67) markers while suppressing astroglia activation (GFAP), indicating enhanced neuronal survival, synaptic remodeling, and hippocampal neurogenesis that collectively supported behavioral recovery. In conclusion, naringin ameliorates CUMS-induced cognitive impairment through inhibition of oxidative stress, inflammation, neurotransmitter imbalance, and enhancing hippocampal neurogenesis.
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