Preventing H₂O₂-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone

Brain Res. 2011 Jun 7;1394:14-23. doi: 10.1016/j.brainres.2011.02.006. Epub 2011 Feb 9.

Abstract

Oxidative stress-induced apoptosis plays a critical role in the pathogenesis of various neurodegenerative disorders. In this study, the neuroprotective properties of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase (AChE) inhibitor modified from a naturally occurring monomeric analogue, huperzine A, on H₂O₂-induced neurotoxicity were investigated in cerebellar granule neurons (CGNs). Exposure of CGNs to H₂O₂ resulted in apoptosis which could be attenuated by the pre-treatment of B12H (0.3-5 nM) in a concentration-dependent manner. Moreover, tacrine and neostigmine failed to prevent neurotoxicity, indicating that the neuroprotection of B12H might not be due to its inhibitory property of AChE enzymatic activity. Increased activation of extracellular signal-regulated kinase (ERK) and decreased activation of glycogen synthase kinase (GSK) 3β were observed after H₂O₂ exposure, and B12H reversed the altered activation of GSK3β, but not that of ERK. Furthermore, using vascular endothelial growth factor (VEGF), phospho-VEGF receptor-2 (VEGFR-2) antibody, a specific VEGFR-2 inhibitor (PTK787/ZK222584) and specific phosphoinositide 3-kinase inhibitors (LY294002 and wortmannin), it was found that VEGF prevented H₂O₂-induced neuronal loss from activating the VEGF/VEGFR-2 system and that the observed B12H neuroprotective effects might share the same signaling pathway. These findings strongly suggest that B12H prevents H₂O₂-induced neuronal apoptosis independent of inhibiting AChE, but through regulating VEGFR-2/Akt/GSK3β signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blotting, Western
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Hydrogen Peroxide / toxicity
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Oxidants / toxicity
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinolones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Oxidants
  • Quinolones
  • bis(12)-hupyridone
  • Hydrogen Peroxide
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-akt
  • Acetylcholinesterase