Objective To explore the therapeutic effect of lignans extracted from Eucommia Ulmoides Oliver on diabetes encephalopathy(DE)rats and the effects on nuclear factor E2 related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway.Methods A rat model of DE was established,and 48 successfully established DE rats were randomly divided into model group,and low-and high-dose lignans groups(200 and 400 mg/kg),and metformin(200 mg/kg)group,with 12 rats in each group.Another 12 healthy rats served as control group.Each group of rats was giv-en corresponding drug intervention once a day for 6 consecutive weeks.Cognitive and memory abilities,serum levels of IL-6,TNF-α,MDA and SOD,and mRNA and protein levels of Nrf2 and HO-1 in the hippocampus were measured in all groups.Pathological changes of the hippocampus were observed after HE staining.Results Compared with the control group,significantly longer escape latency and increased serum levels of IL-6,TNF-α and MDA,while lower times of crossing original platform,shorter residence duration of original platform quadrant,decreased serum SOD level,and reduced mRNA and protein levels of Nrf2 and HO-1 in the hippocampus were observed in the model group(all P＜0.05).Low-and high-dose lignans treatment reversed all above indica-tors when compared with model group(P＜0.05).What's more,the effects of high-dose lignans treatment were more significant than low-dose treatment in escape latency,serum levels of IL-6,TNF-α and MDA,times through the original platform,residence duration of the original platform quadrant,serum SOD level,and mRNA Nrf2 and HO-1 in the hippocampus(6.07±0.70 vs 4.76± 0.52,30.96±2.96 s vs 23.49±2.60 s,77.02±6.51 U/ml vs 61.71±6.75 U/ml,0.69±0.06 vs 0.49± 0.05,0.74±0.07 vs 0.57±0.06,P＜0.05).Conclusion Eucommia lignans can improve the cogni-tive ability,enhance the antioxidant capacity,inhibit inflammatory response and protect the hippo-campus of DE rats,and the mechanism may be related to the activation of Nrf2/HO-1 signaling pathway.