Diabetic encephalopathy is one of the most prevalent chronic complications of diabetes mellitus (DM), but there is currently no effective method of prevention nor proven therapeutic regimen for it. In this study, we investigated the effects of calycosin on cognitive behavior and the potential mechanism involved in streptozocin-induced diabetic rats. The effects of diabetes and calycosin treatment on spatial learning and memory were evaluated using the Morris Water Maze, passive avoidance and motor coordination tests. Histological analysis of the hippocampus cornu ammonis 1 (CA1) region was conducted in rats. The decreased expression of the synapsin (SYN) and postsynatptic density protein (PSD-95), as well as brain-derived neurotrophic factor (BDNF) in diabetic rats was measured by quantitative real-time PCR and western blot. Treatment with calycosin promoted a reduction in the expression of SYN, PSD-95 and BDNF. In addition, diabetic rats showed increased MDA levels, and decreased SOD levels and GSH-Px activities in the hippocampus, as well as increased AChE activity in the cerebral cortex; these changes were reversed by calycosin supplementation. Thus, the impairment of learning and memory in STZ-induced diabetic rats was alleviated by calycosin, and that the degree of alleviation was associated with oxidative stress. We also found that calycosin treatment significantly stimulated Akt phosphorylation and decreased GSK-3 beta and tau phosphorylation, and that these changes could be restored by the PI3K/Akt inhibitor LY294002. In conclusion, calycosin had a beneficial effect on the amelioration, prevention and treatment of diabetes-associated cognitive deficits, through its involvement in oxidative stress, synaptic function and the PI3K/Akt/GSK-3 beta pathway. (C) 2016 Elsevier Inc. All rights reserved.