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

Eur J Pharmacol. 2009 Jun 24;613(1-3):1-9. doi: 10.1016/j.ejphar.2009.03.054. Epub 2009 Apr 1.

Abstract

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, NaNO(2) and ethanol, respectively. Ellman's assay indicated BZYX exhibited high inhibition on AChE activity. IC(50) values for BZYX: 0.058+/-0.022 microM; donepezil: 0.019+/-0.004 microM; rivastigmine: 3.81+/-2.81 microM; glantamine: 3.01+/-1.85 microM and huperzine A: 0.053+/-0.016 microM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H(2)O(2)) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 microM H(2)O(2), while it significantly increased when the cells were pretreated with 0.1-1.0 microM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (DeltaPsim), scavenged reactive oxygen species formation induced by H(2)O(2) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Benzylidene Compounds / pharmacology*
  • Benzylidene Compounds / therapeutic use
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterase Inhibitors / therapeutic use
  • Drug Design
  • Gene Expression Regulation / drug effects
  • Hydrogen Peroxide / adverse effects*
  • Indenes / pharmacology*
  • Indenes / therapeutic use
  • Learning Disabilities / chemically induced*
  • Learning Disabilities / drug therapy
  • Male
  • Maze Learning / drug effects
  • Membrane Potential, Mitochondrial / drug effects
  • Memory Disorders / chemically induced*
  • Memory Disorders / drug therapy
  • Mice
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • PC12 Cells
  • Proteins / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Scopolamine / adverse effects

Substances

  • 2-(4-((dimethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-1-one
  • Benzylidene Compounds
  • Cholinesterase Inhibitors
  • Indenes
  • Neuroprotective Agents
  • Proteins
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Scopolamine