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

Citrus nippokoreana, a traditional Korean citrus species, is rich in flavonoids and polyphenols with antioxidant properties; however, its neuroprotective potential remains unclear. Neurodegeneration is closely associated with oxidative stress, neuronal apoptosis, and impaired synaptic signaling. In this study, we investigated the effects of C. nippokoreana peel extract (CNE, 30% ethanol) using in vitro and in vivo 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.