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

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.

Targeting Impaired Nutrient Sensing via the Glycogen Synthase Kinase-3 Pathway With Therapeutic Compounds to Prevent or Treat Dementia: A Systematic Review

“…Thirty-two studies from 29 articles were included, investigating impaired nutrient sensing using compounds interfering with the GSK3 pathway on cognition in mice (19 studies), rats (12 studies) and zebrafish [one study ( Koehler et al, 2019 )] ( Table 1 ). The Wistar rat was used most often to study dementia (8 out of 32 studies), whereas the C57BL/6 mice were used to study normal ageing [two studies ( Jiang et al, 2020 ; Zhou et al, 2020 )]. The sample size per treatment group varied between six ( Xu et al, 2018 ; Lin et al, 2021 ) to 20 animals ( Yang et al, 2013 ; Ibrahim et al, 2020 ).…”

“…The sample size per treatment group varied between six ( Xu et al, 2018 ; Lin et al, 2021 ) to 20 animals ( Yang et al, 2013 ; Ibrahim et al, 2020 ). The majority of used animal dementia models were transgenic, overexpressing or producing mutant products of human genes such as amyloid precursor protein (APP) [ Jiang et al, 2020 ; Zhou et al, 2020 ; Lin et al, 2021 ) and tau ( Zhang et al, 2018 )]. Dementia was also induced by administration of intracerebroventricular Aβ ( Huang et al, 2019 ; Akhtar et al, 2020 ; Fan et al, 2020 ; Sun et al, 2020 ; Yan et al, 2021 ) or streptozotocin ( Tang et al, 2018 ; Wang et al, 2018 ; Zhu et al, 2019 ; Akhtar et al, 2020 ).…”

“…Ten out of 32 studies tested synthetic compounds including: SCR-1693 ( Bi et al, 2020 ), an acetylcholinesterase inhibitor and calcium channel blocker; brain-derived neurotrophic factor (BDNF) ( Xu et al, 2018 ); α-Lipoic acid ( Zhang et al, 2018 ); diapocynin ( Ibrahim et al, 2020 ), a NOX inhibitor, sodium orthovanadate ( Akhtar et al, 2020 ), a tyrosine phosphatase inhibitor; DL0410 ( Zhou et al, 2020 ) cholinesterase inhibitor; 2-APB ( Thapak et al, 2020 ), which inhibit both inositol trisphosphate (IP3) receptors and transient receptor potential (TRP) channels; LMDS-1 ( Fan et al, 2020 ), a potential TrkB receptor agonist and TDZD-8 ( Koehler et al, 2019 ), a selective non-ATP competitive inhibitor of glycogen synthase kinase 3 beta (GSK3β).…”

“…Six studies ( Zhang et al, 2018 ; Akhtar et al, 2020 ; Bi et al, 2020 ; Thapak et al, 2020 ; Zhou et al, 2020 ; Wang et al, 2021 ) investigated a dose-response relationship. For SCR-1693 ( Bi et al, 2020 ), a higher dose gave better cognitive outcomes.…”

“…The following compounds improved spatial memory: α-Lipoic acid, BDNF, sodium orthovanadate, SCR-1693, diapocynin, DL0410, 2-APB ( Xu et al, 2018 ; Zhang et al, 2018 ; Akhtar et al, 2020 ; Bi et al, 2020 ; Ibrahim et al, 2020 ; Thapak et al, 2020 ; Zhou et al, 2020 ). Sodium orthovanadate showed improvement in recognition memory ( Akhtar et al, 2020 ).…”