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

Wei Cui, Wenming Li, Yuming Zhao, Shinghung Mak, Yang Gao, Jialie Luo, Huan Zhang, Yuqing Liu, Paul R. Carlier, Jianhui Rong, Yifan Han

Research output: Journal article publicationJournal articleAcademic researchpeer-review

22 Citations (Scopus)

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 H2O2resulted 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 H2O2exposure, 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.
Original languageEnglish
Pages (from-to)14-23
Number of pages10
JournalBrain Research
Volume1394
DOIs
Publication statusPublished - 7 Jun 2011

Keywords

  • Bis(12)-hupyridone
  • Hydrogen peroxide
  • Neurodegenerative disorder
  • Oxidative stress
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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