Trilobatin rescues cognitive impairment of Alzheimer's disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway.

Abstract

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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 10 Pg. 2482-2494 (Oct 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 35292770 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Chemical References

• Amyloid beta-Peptides
• Flavonoids
• Food Additives
• HMGB1 Protein
• NF-kappa B
• Neuroprotective Agents
• Polyphenols
• Sirt3 protein, mouse
• Toll-Like Receptor 4
• trilobatin
• Superoxide Dismutase
• superoxide dismutase 2
• Sirtuin 3

Topics

• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides
• Animals
• Cognitive Dysfunction (drug therapy)
• Disease Models, Animal
• Flavonoids
• Food Additives (pharmacology, therapeutic use)
• HMGB1 Protein (metabolism)
• Mice
• Mice, Transgenic
• Molecular Docking Simulation
• NF-kappa B (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Polyphenols
• Rats
• Signal Transduction
• Sirtuin 3 (drug effects, metabolism)
• Superoxide Dismutase (drug effects, metabolism)
• Toll-Like Receptor 4 (metabolism)