Alzheimer's disease(AD)is a progressive neurodegenerative disorder with cognitive impairment that currently is uncurable.Previous study shows that trilobatin(TLB),a naturally occurring food additive,exerts neuroprotective effect in experimental models of AD.In the present study we investigated the molecular mechanisms underlying the beneficial effect of TLB on experimental models of AD in vivo and in vitro.APP/PS1 transgenic mice were administered TLB(4,8 mg·kg-1·d-1,i.g.)for 3 months;rats were subjected to ICV injection of Aβ25-35,followed by administration of TLB(2.5,5,10 mg·kg-1·d-1,i.g.)for 14 days.We showed that TLB administration significantly and dose-dependently ameliorated the cognitive deficits in the two AD animal models,assessed in open field test,novel object recognition test,Y-maze test and Morris water maze test.Furthermore,TLB administration dose-dependently inhibited microglia and astrocyte activation in the hippocampus of APP/PS1 transgenic mice accompanied by decreased expression of high-mobility group box 1(HMGB1),TLR4 and NF-κB.In Aβ25-25-treated BV2 cells,TLB(12.5-50 μM)concentration-dependently increased the cell viability through inhibiting HMGB1/TLR4/NF-κB signaling pathway.HMGB1 overexpression abrogated the beneficial effects of TLB on BV2 cells after Aβ25-35 insults.Molecular docking and surface plasmon resonance assay revealed that TLB directly bound to HMGB1 with a KD value of 8.541×10-4 M.Furthermore,we demonstrated that TLB inhibited Aβ25-35-induced acetylation of HMGB1 through activating SIRT3/SOD2 signaling pathway,thereby restoring redox homeostasis and suppressing neuroinflammation.These results,for the first time,unravel a new property of TLB:rescuing cognitive impairment of AD via targeting HMGB1 and activating SIRT3/SOD2 signaling pathway.

Jian-mei Gao;Xun Zhang;Guo-tao Shu;Na-na Chen;Jian-yong Zhang;Fan Xu;Fei Li;Yuan-gui Liu;Yu Wei;Yu-qi He;Jing-shan Shi;Qi-hai Gong

Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi 563000,China;Department of Clinical Pharmacotherapeutics,School of Pharmacy,Zunyi Medical University,Zunyi 563000,China;Spemann Graduate School of Biology and Medicine(SGBM),Albert Ludwigs University Freiburg,79085 Freiburg,Germany;Department of Neurology,The Affiliated Hospital of Zunyi Medical University,Zunyi 563000,China

中国药理学报（英文版）

[1]Jian-mei Gao;Xun Zhang;Guo-tao Shu;Na-na Chen;Jian-yong Zhang;Fan Xu;Fei Li;Yuan-gui Liu;Yu Wei;Yu-qi He;Jing-shan Shi;Qi-hai Gong-.Trilobatin rescues cognitive impairment of Alzheimer's disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway)[J].中国药理学报（英文版）,2022(10):2482-2494

Trilobatin,uncurable,trilobatin

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