Title : Preventing H(2)O(2)-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2\/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone - Cui_2011_Brain.Res_1394_14 |
Author(s) : Cui W , Li W , Zhao Y , Mak SH , Gao Y , Luo J , Zhang H , Liu Y , Carlier PR , Rong J , Han YF |
Ref : Brain Research , 1394 :14 , 2011 |
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 H(2)O(2)-induced neurotoxicity were investigated in cerebellar granule neurons (CGNs). Exposure of CGNs to H(2)O(2) 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) 3beta were observed after H(2)O(2) exposure, and B12H reversed the altered activation of GSK3beta, 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 H(2)O(2)-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 H(2)O(2)-induced neuronal apoptosis independent of inhibiting AChE, but through regulating VEGFR-2/Akt/GSK3beta signaling pathway. |
PubMedSearch : Cui_2011_Brain.Res_1394_14 |
PubMedID: 21315693 |
Cui W, Li W, Zhao Y, Mak SH, Gao Y, Luo J, Zhang H, Liu Y, Carlier PR, Rong J, Han YF (2011)
Preventing H(2)O(2)-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2\/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone
Brain Research
1394 :14
Cui W, Li W, Zhao Y, Mak SH, Gao Y, Luo J, Zhang H, Liu Y, Carlier PR, Rong J, Han YF (2011)
Brain Research
1394 :14