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

TitlePreventing H2O2-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone
Authors
KeywordsBis(12)-hupyridone
Hydrogen peroxide
Neurodegenerative disorder
Oxidative stress
Vascular endothelial growth factor
Issue Date2011
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/brainres
Citation
Brain Research, 2011, v. 1394, p. 14-23 How to Cite?
AbstractOxidative 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 2O 2-induced neurotoxicity were investigated in cerebellar granule neurons (CGNs). Exposure of CGNs to H 2O 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) 3β were observed after H 2O 2 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 H 2O 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 2O 2-induced neuronal apoptosis independent of inhibiting AChE, but through regulating VEGFR-2/Akt/GSK3β signaling pathway. © 2011 Elsevier B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/136304
ISSN
2015 Impact Factor: 2.561
2015 SCImago Journal Rankings: 1.351
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong KongPolyU6608/07M
5609/09M
N_PolyU618/07
AoE/B15/01-II
Hong Kong Polytechnic UniversityG-YX96
G-YH19
Shenzhen Shuangbai Funding Scheme
Funding Information:

This work was supported by grants from the Research Grants Council of Hong Kong (PolyU6608/07M, 5609/09M; N_PolyU618/07 and AoE/B15/01-II), The Hong Kong Polytechnic University (G-YX96 and G-YH19) and the Shenzhen Shuangbai Funding Scheme 2008. We sincerely thank Prof. Moussa Youdim for kindly providing suggestions during this study.

References

 

DC FieldValueLanguage
dc.contributor.authorCui, Wen_HK
dc.contributor.authorLi, Wen_HK
dc.contributor.authorZhao, Yen_HK
dc.contributor.authorMak, Sen_HK
dc.contributor.authorGao, Yen_HK
dc.contributor.authorLuo, Jen_HK
dc.contributor.authorZhang, Hen_HK
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorCarlier, PRen_HK
dc.contributor.authorRong, Jen_HK
dc.contributor.authorHan, Yen_HK
dc.date.accessioned2011-07-27T02:12:52Z-
dc.date.available2011-07-27T02:12:52Z-
dc.date.issued2011en_HK
dc.identifier.citationBrain Research, 2011, v. 1394, p. 14-23en_HK
dc.identifier.issn0006-8993en_HK
dc.identifier.urihttp://hdl.handle.net/10722/136304-
dc.description.abstractOxidative 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 2O 2-induced neurotoxicity were investigated in cerebellar granule neurons (CGNs). Exposure of CGNs to H 2O 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) 3β were observed after H 2O 2 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 H 2O 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 2O 2-induced neuronal apoptosis independent of inhibiting AChE, but through regulating VEGFR-2/Akt/GSK3β signaling pathway. © 2011 Elsevier B.V. All rights reserved.en_HK
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/brainresen_HK
dc.relation.ispartofBrain Researchen_HK
dc.subjectBis(12)-hupyridoneen_HK
dc.subjectHydrogen peroxideen_HK
dc.subjectNeurodegenerative disorderen_HK
dc.subjectOxidative stressen_HK
dc.subjectVascular endothelial growth factoren_HK
dc.titlePreventing H2O2-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridoneen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-8993&volume=1394&spage=14&epage=23&date=2011&atitle=Preventing+H2O2-induced+apoptosis+in+cerebellar+granule+neurons+by+regulating+the+VEGFR-2/Akt+signaling+pathway+using+a+novel+dimeric+antiacetylcholinesterase+bis(12)-hupyridoneen_US
dc.identifier.emailRong, J: jrong@hku.hken_HK
dc.identifier.authorityRong, J=rp00515en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.brainres.2011.02.006en_HK
dc.identifier.pmid21315693-
dc.identifier.scopuseid_2-s2.0-79956272964en_HK
dc.identifier.hkuros187387en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79956272964&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume1394en_HK
dc.identifier.spage14en_HK
dc.identifier.epage23en_HK
dc.identifier.isiWOS:000291836200002-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridCui, W=35191650200en_HK
dc.identifier.scopusauthoridLi, W=35741086500en_HK
dc.identifier.scopusauthoridZhao, Y=47761550000en_HK
dc.identifier.scopusauthoridMak, S=35741097300en_HK
dc.identifier.scopusauthoridGao, Y=35227272200en_HK
dc.identifier.scopusauthoridLuo, J=8720127800en_HK
dc.identifier.scopusauthoridZhang, H=37762530600en_HK
dc.identifier.scopusauthoridLiu, Y=47761180400en_HK
dc.identifier.scopusauthoridCarlier, PR=7102383847en_HK
dc.identifier.scopusauthoridRong, J=7005980047en_HK
dc.identifier.scopusauthoridHan, Y=8527680500en_HK
dc.identifier.citeulike8833857-

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