Hesperetin improves cognitive impairment in scopolamine-induced C57BL/6 mice

Background: Cognitive impairment limits daily functioning and is closely linked to neuroinflammation and neuronal death caused by oxidative stress. Hesperetin, a bioactive flavonoid aglycone from citrus peels, remains relatively unexplored despite its therapeutic potential. Objective: This study evaluated hesperetin in scopolamine (SCO)-induced cognitive impairment in C57BL/6 mice. Design: Memory impairment was induced using SCO (1 mg/kg). Mice were divided into control (n = 10), SCO (n = 10), and SCO with hesperetin (25 or 50 mg/kg/day, n = 10) groups. Treatments were administered daily for 28 days. Spatial memory performance was assessed using the Y-maze test. Brain histology was examined through hematoxylin and eosin staining. Malondialdehyde (MDA) levels were measured to evaluate lipid peroxidation, and acetylcholinesterase (AChE) activity was analyzed. The underlying mechanism was investigated using Western blotting and quantitative polymerase chain reaction, focusing on the AKT (protein kinase B)/CREB (cAMP-response element binding protein)/BDNF (brain-derived neurotrophic factor) signaling pathway. Results: Hesperetin significantly improved cognition, increasing spontaneous alternation in the Y-maze (P < 0.05). It also mitigated histopathological changes, such as neuronal contraction and morphological abnormalities, and improved lipid profiles. Hesperetin reduced AChE activity, MDA levels, and the expression of proinflammatory markers (tumor necrosis factor-α, cyclooxygenase-2, and nuclear factor-κB). The AKT/CREB/BDNF pathway, critical for long-term memory formation, was activated by hesperetin through increased phosphorylation of AKT and CREB and elevated BDNF expression. Hesperetin enhanced H3K9 and H3K27 acetylation, reduced H3K4 and H3K27 dimethylation, and restored sirtuin 1–histone deacetylase balance, all of which are associated with memory formation. Conclusion: Overall, hesperetin improved cognition in SCO-treated mice, highlighting its potential as a therapeutic candidate for neurodegenerative disorders