Kim_2025_Mol.Med.Rep_31_

The aging process is associated with a decline in certain cognitive abilities, including learning and memory. This agerelated cognitive decline is associated with a reduction in neurogenesis and alterations in the cholinergic system. Humulus japonicus (HJ), an ornamental plant in the family Cannabaceae, has been reported to exert beneficial effects against neurodegenerative pathophysiologies in mouse models of disorders such as Alzheimer's and Parkinson's disease. Despite the increasingly aging populations of numerous societies, no study has yet investigated the effects of HJ on cognitive decline associated with normal aging. The present study therefore aimed to examine the protective potential of HJ water (HJW) extract against agerelated cognitive decline and scopolamineinduced cognitive impairment. The analyses revealed that the oral administration of HJW markedly improved novel objective recognition and spatial learning in the novel object recognition and Morris water maze tests, respectively, in aged mice. The administration of 600 mg/kg HJW further increased neurogenesis and CA1 thickness in the hippocampi of aged mice. In scopolamineinduced cognitive impairment, administration of 400 or 600 mg/kg HJW markedly increased novel object recognition performance in scopolaminetreated mice. The inhibitory effect of HJW on acetylcholinesterase (AChE) and the activation effects of HJW on the calcium/calmodulindependent kinase (CaMK)IIalphacAMP response elementbinding protein (CREB) and AKTglycogen synthase kinase3 beta (GSK3beta) pathways were further demonstrated. Overall, these results indicate that HJW administration improves cognitive function through the regulation of AChE activity and CaMKIIalphaCREB and AKTGSK3beta pathways.