DL-3-n-Butylphthalide(DL-NBP),a small molecular compound extracted from the seeds of Apium graveolens Linn(Chinese celery),has been shown to exert neuroprotective effects due to its anti-inflammatory,anti-oxidative and anti-apoptotic activities.DL-NBP not only protects against ischemic cerebral injury,but also ameliorates vascular cognitive impairment in dementia patients including AD and PD.In the current study,we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline(DACD)in db/db mice,a model of type-2 diabetes.db/db mice were orally administered DL-NBP(20,60,120 mg·kg-1·d-1)for 8 weeks.Then the mice were subjected to behavioral test,their brain tissue was collected for morphological and biochemical analyses.We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing.Furthermore,DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95,synaptophysin and synapsin-1 as well as dendritic density in the hippocampus,especially at a dose of 60 mg/kg.Moreover,we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling,and increased brain-derived neurotrophic factor(BDNF)expression by activating PI3K/Akt/CREB signaling in the hippocampus.These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells.Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.