Cognitive-Enhancing Effects of Hesperetin-Rich CNE against Neuronal Damage and Memory Impairment by Regulating AKT/Nrf2 and BDNF/CREB Signaling

models. CNE significantly protected HT22 hippocampal neurons against glutamate-induced oxidative stress by reducing intracellular reactive oxygen species (ROS) and apoptosis, while regulating AKT/Nrf2-associated antioxidant pathways and enhancing BDNF/CREB signaling. In a scopolamine-induced mouse model, oral administration of CNE (50 or 100 mg/kg/day) improved cognitive performance in behavioral tests. CNE also restored the expression of BDNF, CREB, and HO-1, and reduced acetylcholinesterase activity in the hippocampus. Histological analysis confirmed reduced neuronal damage. Furthermore, serum metabolomics revealed modulation of tryptophan metabolism, phosphatidylcholine species, and redox-related pathways. To explore constituents potentially contributing to the neuroprotective effects of CNE, major compounds identified by phytochemical profiling were screened in glutamate-induced HT22 cells. Several phytochemicals exhibited protective effects, suggesting that the biological activity of CNE may result from the combined actions of multiple constituents rather than a single compound. These findings suggest that CNE attenuates oxidative stress-induced neuronal damage and improves cognitive function through coordinated regulation of antioxidant defense, neurotrophic signaling, and cholinergic function.