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AIM Kangen-karyu (Guan-Yuan-Ke-Li; KK) is a Chinese prescription consisting of six crude drugs such as Salviae Miltiorrhizae Radix.KK reportedly inhibits platelet aggregation and protects cognitive function form cerebral ischemia.However, little information is available on a therapeutic effect of KK on cognitive deficits.We studied if KK has an ameliorative effect on cognitive deficits in animal models of dementia and if so, what is the molecular mechanism underlying the effect.METHODS We investigated neuropharmacologically the effects of CTS on cognitive performance using a senescence accelerated prone mouse SAMP8 and type 2 diabetic db/db mice because aging and diabetes are risk factors for dementia.RESULTS Compared with their age-matched control strain mice, the model animals exhibited cognitive deficits in the object recognition test or water maze test.Daily administration of KK (100-200 mg· kg-1, po) and the acetylcholinesterase inhibitor tacrine (THA, 2.5 mg· kg-1, ip) ameliorated the deficits observed in the models.KK reversed downregulation of biochemical factors related to neuroplasticity and learning and memory such as central cholinergic marker proteins, brain-derived neurotrophic factor, and vascular endothelial growth factor (VEGF) systems.CONCLUSION Our findings suggest that KK ameliorates aging-and diabetes-induced cognitive deficits by attenuating dysfunction of central cholinergic systems, neuroplasticity-related neuronal signaling, and VEGF systems.