DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission and reducing neuronal loss.

Content Provider	Europe PMC
Author	Zhou, Wei Lian, Wen-wen Yan, Rong Jia, Hao Xu, Lv-jie Wang, Lin Liu, Ai-lin Du, Guan-hua
Abstract	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, 30 mg· kg−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-3β 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 Aβ deposition, inhibited glial overactivation, and the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. We conclude that DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission via activating the AKT/GSK-3β 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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ISSN	16714083
Journal	Acta Pharmacologica Sinica [Acta Pharmacol Sin]
Volume Number	41
DOI	10.1038/s41401-019-0312-y
PubMed Central reference number	PMC7471418
Issue Number	5
PubMed reference number	31685977
e-ISSN	17457254
Language	English
Publisher	Springer Singapore
Publisher Date	2019-11-04
Publisher Place	Singapore
Access Restriction	Open
Rights License	© CPS and SIMM 2019
Subject Keyword	DL0410 Alzheimer’s disease cognitive deficits long-term potentiation synaptic transmission neuronal loss APP/PS1 transgenic mice
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)