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Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: role of microglial NADPH oxidase.

DC Field Value Language
dc.contributor.authorChoi, SH-
dc.contributor.authorLee, DY-
dc.contributor.authorKim, SU-
dc.contributor.authorJin, BK-
dc.date.accessioned2011-07-08T01:39:41Z-
dc.date.available2011-07-08T01:39:41Z-
dc.date.issued2005-
dc.identifier.issn0270-6474-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/3249-
dc.description.abstractThe present study investigated whether thrombin, a potent microglial activator, can induce reactive oxygen species (ROS) generation through activation of microglial NADPH oxidase and if this may contribute to oxidative damage and consequent neurodegeneration. Seven days after intrahippocampal injection of thrombin, Nissl staining and immunohistochemistry using the neuronal-specific nuclear protein NeuN revealed a significant loss in hippocampal CA1 neurons. In parallel, thrombin-activated microglia, assessed by OX-42 and OX-6 immunohistochemistry, and ROS production, assessed by hydroethidine histochemistry, were observed in the hippocampal CA1 area in which degeneration of hippocampal neurons occurred. Reverse transcription-PCR at various time points after thrombin administration demonstrated an early and transient expression of inducible nitric oxide synthase (iNOS) and several proinflammatory cytokines. Western blot analysis and double-label immunohistochemistry showed an increase in the expression of and the localization of iNOS within microglia. Additional studies demonstrated that thrombin induced the upregulation of membrane (gp91(phox)) and cytosolic (p47(phox) and p67(phox)) components, translocation of cytosolic proteins (p47(phox), p67(phox), and Rac1) to the membrane, and p67(phox) expression of the NADPH oxidase in microglia in the hippocampus in vivo, indicating the activation of NADPH oxidase. The thrombin-induced oxidation of proteins and loss of hippocampal CA1 neurons were partially inhibited by an NADPH oxidase inhibitor and by an antioxidant. To our knowledge, the present study is the first to demonstrate that thrombin-induced neurotoxicity in the hippocampus in vivo is caused by microglial NADPH oxidase-mediated oxidative stress. This suggests that thrombin inhibition or enhancing antioxidants may be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer's disease, that are associated with microglial-derived oxidative damage.-
dc.language.isoen-
dc.subject.MESHAnalysis of Variance-
dc.subject.MESHAnimals-
dc.subject.MESHAnimals, Newborn-
dc.subject.MESHAntigens, CD-
dc.subject.MESHAntioxidants-
dc.subject.MESHBlotting, Western-
dc.subject.MESHCell Count-
dc.subject.MESHCell Death-
dc.subject.MESHCells, Cultured-
dc.subject.MESHChromans-
dc.subject.MESHDose-Response Relationship, Drug-
dc.subject.MESHDrug Interactions-
dc.subject.MESHEnzyme Inhibitors-
dc.subject.MESHGene Expression Regulation-
dc.subject.MESHHippocampus-
dc.subject.MESHImmunohistochemistry-
dc.subject.MESHIndoles-
dc.subject.MESHMicroglia-
dc.subject.MESHNADPH Oxidase-
dc.subject.MESHNeurons-
dc.subject.MESHNitric Oxide Synthase Type II-
dc.subject.MESHOxidative Stress-
dc.subject.MESHPhosphoproteins-
dc.subject.MESHPhosphopyruvate Hydratase-
dc.subject.MESHRNA, Messenger-
dc.subject.MESHRats-
dc.subject.MESHRats, Sprague-Dawley-
dc.subject.MESHReverse Transcriptase Polymerase Chain Reaction-
dc.subject.MESHThrombin-
dc.subject.MESHTime Factors-
dc.titleThrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: role of microglial NADPH oxidase.-
dc.typeArticle-
dc.identifier.pmid15843610-
dc.identifier.urlhttp://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15843610-
dc.contributor.affiliatedAuthor김, 승업-
dc.contributor.affiliatedAuthor진, 병관-
dc.type.localJournal Papers-
dc.identifier.doi10.1523/JNEUROSCI.4306-04.2005-
dc.citation.titleThe Journal of neuroscience-
dc.citation.volume25-
dc.citation.number16-
dc.citation.date2005-
dc.citation.startPage4082-
dc.citation.endPage4090-
dc.identifier.bibliographicCitationThe Journal of neuroscience, 25(16). : 4082-4090, 2005-
dc.identifier.eissn1529-2401-
dc.relation.journalidJ002706474-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
Journal Papers > Research Organization > Institute for Medical Sciences
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