DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway.

Abstract

1,1'-([1,1'-Biphenyl]-4,4'-diyl)bis(3-(piperidin-1-yl)propan-1-one)dihydrochloride (DL0410) is a novel synthetic dual acetylcholinesterase (AChE)/butyrocholinesterase (BuChE) inhibitor, which has shown a potential therapeutic effect on Alzheimer's disease (AD). In this study we examined whether DL0410 produced neuroprotective effects in an AD cellular model and an Aβ1-42-induced amnesia mouse model. The in vitro inhibitory activities against AChE and BuChE were estimated using Ellman's assay. Copper-induced toxicity in APPsw-SY5Y cells was used as AD cellular model, the cell viability was assessed using MTS assay, and cell apoptosis was evaluated based on mitochondrial membrane potential detection. Aβ1-42-induced amnesia mouse model was made in male mice by injecting aggregated Aβ1-42 (2 μg in 2 μL 0.1% DMSO) into the right cerebral ventricle. Before and after Aβ1-42 injection, the mice were orally administered DL0410 (1, 3, 9 mg·kg-1·d-1) or rivastigmine (2 mg·kg-1·d-1) for 3 and 11 d, respectively. Memory impairments were examined using Morris water maze (MWM) test and passive avoidance test. The expression levels of APP, CREB, BDNF, JNK and Akt in the mouse brains were measured with either immunohistochemistry or Western blotting. DL0410 exhibited in vitro inhibitory abilities against AChE and BuChE with IC50 values of 0.286±0.004 and 3.962±0.099 μmol/L, respectively, which were comparable to those of donepezil and rivastigmine. In APPsw-SY5Y cells, pretreatment with DL0410 (1, 3, and 10 μmol/L) decreased the phosphorylation of JNK and increased the phosphorylation of Akt, markedly decreased copper-stimulated Aβ1-42 production, reversed the loss of mitochondrial membrane potential, and dose-dependently increased the cell viability. In Aβ1-42-treated mice, DL0410 administration significantly ameliorated learning and memory deficits in MWM test and passive avoidance test. Furthermore, DL0410 administration markedly decreased Aβ1-40/42 deposits in mouse cerebral cortices, and significantly up-regulated neurotrophic CREB/BDNF. Meanwhile, Akt/JNK signaling pathway may play a key role in the neuroprotective effect of DL0410. DL0410 ameliorates cognitive deficit and exerts neuronal protection in AD models, implicating this compound as a candidate drug for the prevention and therapy of AD.