DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress  

作　　者：Bei-ni Wang Cheng-biao Wu Zi-miao Chen Pei-pei Zheng Ya-qian Liu Jun Xiong Jing-yu Xu Pei-feng Li Abdullah Al Mamun Li-bing Ye Zhi-long Zheng Yan-qing Wu Jian Xiao Jian Wang 

机构地区：[1]Department of Hand Surgery and Peripheral Neurosurgery,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325000,China [2]School of Pharmaceutical Science,Wenzhou Medical University,Wenzhou 325000,China [3]Research Center,Affiliated Xiangshan Hospital,Wenzhou Medical University,Ningbo 315700,China [4]The Institute of Life Sciences,Engineering Laboratory of Zhejiang province for Pharmaceutical Development of Growth Factors,Biomedical Collaborative Innovation Center of Wenzhou,Wenzhou University,Wenzhou 325035,China

出　　处：《Acta Pharmacologica Sinica》2021年第3期347-360,共14页中国药理学报（英文版）

基　　金：supported by the research grants from the National Natural Science Foundation of China(81801233,81870842,81801245,81802238);Natural Science Foundation of Zhejiang Province(LQ18H090011 and LGD21H070001).

摘　　要：DL3-n-Butylphthalide(DLNBP),a small molecular compound extracted from the seeds of Ap/um graveo/ens 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.

关 键 词：diabetes-associated cognitive decline DL-3-n-butylphthalide cognitive function hippocampus BDNF oxidative stress neuroprotection 

分 类 号：R96[医药卫生—药理学] R587.1[医药卫生—药学]