BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide

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BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO2 and ethanol, respectively. Ellman's assay indicated BZYX exhibited high inhibition on AChE activity. IC50 values for BZYX: 0.058 ± 0.022 μM; donepezil: 0.019 ± 0.004 μM; rivastigmine: 3.81 ± 2.81 μM; glantamine: 3.01 ± 1.85 μM and huperzine A: 0.053 ± 0.016 μM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H2O2) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 μM H2O2, while it significantly increased when the cells were pretreated with 0.1–1.0 μM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (ΔΨm), scavenged reactive oxygen species formation induced by H2O2 and resulted in up-regulation of procaspase3 and xIAP protein level and down-regulation of phosphorylated JNK protein, p53 protein level and cleavage of caspase 3. It is speculated that the mitochondrial pathway, mediated by Bcl-2 family and Mitogen-Activated Protein Kinases (MAPKs), might involved in the neuroprotection of BZYX. These results first demonstrated that BZYX had neuroprotective effects as well as cognition enhancement and acetylcholinesterase inhibition. It is hopeful that BZYX becomes a potential candidate for use in the intervention for neurodegenerative diseases.

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