Journal
ACTA PHARMACOLOGICA SINICA
Volume 41, Issue 5, Pages 599-611Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41401-019-0312-y
Keywords
DL0410; Alzheimer's disease; cognitive deficits; long-term potentiation; synaptic transmission; neuronal loss; APP; PS1 transgenic mice
Funding
- National Great Science Technology Projects [2014ZX09507003-002]
- Drug Innovation Major Project [2018ZX09711001-003-002]
- CAMS Initiative for Innovative Medicine (CAMS-IZM) [2016-IZM-3-007]
- Beijing National Science Foundation [7152103]
- National Natural Science Foundation of China [81673480]
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At present, few available drugs can be used to either improve pathological features or prevent the progression of Alzheimer's disease (AD). DL0410 ((1,1 '-([1,1 '-biphenyl]-4,4 '-diyl) bis (3-(piperidin-1-yl) propan-1-one) dihydrochloride) is a multiple-target small molecule that has been found to reverse cognitive impairment in different animal models of AD. In this study we evaluated the cognition-improving effects of DL0410 in APP/PS1 transgenic mice and explored the underlying mechanisms. APP/PS1 transgenic mice were administered DL0410 (3, 10, 30mgkg(-1)d(-1), ig) for 2 months. We found that DL0410 administration significantly ameliorated cognitive deficits in both the nest-building and Morris water maze tests. In electrophysiological analysis of hippocampal slices, we showed that DL0410 administration significantly enhanced the field EPSP slope and HFS-induced LTP in CA1 area. Furthermore, we revealed that DL0410 administration significantly increased the phosphorylation of AKT and the activity of GSK-3 beta in the hippocampus and cortex. Moreover, DL0410 administration dose-dependently increased the expression level of phosphorylated ERK1/2 in the hippocampus and cortex. In addition, DL0410 dose-dependently decreased the neuronal loss by decreasing the production of A beta deposition, inhibited glial overactivation, and the production of inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6. We conclude that DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission via activating the AKT/GSK-3 beta and MAPK/ERK signaling pathway and reducing neuronal loss. DL0410 may be an effective agent for AD treatment in the future.
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