Sorbus commixta Fruit Extract Ameliorates Corticosterone-Induced Cognitive Impairment by Activating the BDNF-TrkB-PI3K-Akt-CREB Pathway

Elevated corticosterone (CORT) levels from chronic stress or depression impair cognitive function and neuronal survival by suppressing brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and the cAMP response element-binding protein (CREB) signaling pathway. The present study evaluated the neuroprotective effects of Sorbus commixta fruit extract (SCE) in CORT-induced HT22 hippocampal cells and a CORT-induced depression-like mouse model. In vitro , SCE pretreatment (100 or 200 μg/mL) protected against CORT-induced cytotoxicity and intracellular stress. Notably, SCE prevented CORT-mediated downregulation of microtubule-associated protein 2 ( Map2 ) and Bdnf mRNA and BDNF protein levels, and maintained the phosphorylation ratios of TrkB, phosphoinositide 3-kinase (PI3K), serine/threonine protein kinase B (Akt), and CREB. Wortmannin diminished the SCE-associated restoration of PI3K, Akt, and CREB phosphorylation, supporting the involvement of PI3K-Akt signaling. In vivo , oral administration of SCE (100 or 300 mg/kg) attenuated CORT-induced anhedonia-like behavior and impairments in learning and spatial working memory. These behavioral effects were accompanied by preservation of hippocampal BDNF-TrkB-PI3K-Akt-CREB signaling. Collectively, these findings suggest that SCE attenuates CORT-induced cellular stress, disruption of neuroplasticity-related signaling, and behavioral impairments, potentially by modulating the BDNF-TrkB-PI3K-Akt-CREB pathway. Therefore, SCE is a promising functional food-derived material for supporting neuronal plasticity under chronic stress conditions.