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Prothrombin kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation.
DC Field | Value | Language |
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dc.contributor.author | Kim, SR | - |
dc.contributor.author | Chung, ES | - |
dc.contributor.author | Bok, E | - |
dc.contributor.author | Baik, HH | - |
dc.contributor.author | Chung, YC | - |
dc.contributor.author | Won, SY | - |
dc.contributor.author | Joe, E | - |
dc.contributor.author | Kim, TH | - |
dc.contributor.author | Kim, SS | - |
dc.contributor.author | Jin, MY | - |
dc.contributor.author | Choi, SH | - |
dc.contributor.author | Jin, BK | - |
dc.date.accessioned | 2011-04-28T04:37:18Z | - |
dc.date.available | 2011-04-28T04:37:18Z | - |
dc.date.issued | 2010 | - |
dc.identifier.issn | 0360-4012 | - |
dc.identifier.uri | http://repository.ajou.ac.kr/handle/201003/2489 | - |
dc.description.abstract | We have shown that prothrombin kringle-2 (pKr-2), a domain of human prothrombin distinct from thrombin could activate cultured rat brain microglia in vitro. However, little is known whether pKr-2-induced microglial activation could cause neurotoxicity on dopaminergic (DA) neurons in vivo. To address this question, pKr-2 was injected into the rat substantia nigra (SN). Tyrosine hydroxylase (TH) immunohistochemistry experiments demonstrate significant loss of DA neurons seven days after injection of pKr-2. In parallel, pKr-2-activated microglia were detected in the SN with OX-42 and OX-6 immunohistochemistry. Reverse transcription PCR and double-label immunohistochemistry revealed that activated microglia in vivo exhibit early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and several proinflammatory cytokines. The pKr-2-induced loss of SN DA neurons was partially inhibited by the NOS inhibitor N(G)-nitro-L-arginine methyl ester hydrochloride, and the COX-2 inhibitor DuP-697. Extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were activated in the SN as early as 1 hr after pKr-2 injection, and localized within microglia. Inhibition of these kinases led to attenuation of mRNA expression of iNOS, COX-2 and several proinflammatory cytokines, and rescue of DA neurons in the SN. Intriguingly, following treatment with pKr-2 in vitro, neurotoxicity was detected exclusively in co-cultures of mesencephalic neurons and microglia, but not microglia-free neuron-enriched mesencephalic cultures, indicating that microglia are required for pKr-2 neurotoxicity. Our results strongly suggest that microglia activated by endogenous compound(s), such as pKr-2, are implicated in the DA neuronal cell death in the SN. | - |
dc.language.iso | en | - |
dc.subject.MESH | Animals | - |
dc.subject.MESH | Antigens, CD11b | - |
dc.subject.MESH | Cells, Cultured | - |
dc.subject.MESH | Coculture Techniques | - |
dc.subject.MESH | Cyclooxygenase 2 | - |
dc.subject.MESH | Cyclooxygenase 2 Inhibitors | - |
dc.subject.MESH | Dopamine | - |
dc.subject.MESH | Female | - |
dc.subject.MESH | Gliosis | - |
dc.subject.MESH | Inflammation Mediators | - |
dc.subject.MESH | Kringles | - |
dc.subject.MESH | MAP Kinase Signaling System | - |
dc.subject.MESH | Microglia | - |
dc.subject.MESH | Neurons | - |
dc.subject.MESH | Nitric Oxide Synthase | - |
dc.subject.MESH | Nitric Oxide Synthase Type II | - |
dc.subject.MESH | Parkinson Disease | - |
dc.subject.MESH | Prothrombin | - |
dc.subject.MESH | RNA, Messenger | - |
dc.subject.MESH | Rats | - |
dc.subject.MESH | Rats, Sprague-Dawley | - |
dc.subject.MESH | Substantia Nigra | - |
dc.title | Prothrombin kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation. | - |
dc.type | Article | - |
dc.identifier.pmid | 20025058 | - |
dc.contributor.affiliatedAuthor | 조, 은혜 | - |
dc.type.local | Journal Papers | - |
dc.identifier.doi | 10.1002/jnr.22318 | - |
dc.citation.title | Journal of neuroscience research | - |
dc.citation.volume | 88 | - |
dc.citation.number | 7 | - |
dc.citation.date | 2010 | - |
dc.citation.startPage | 1537 | - |
dc.citation.endPage | 1548 | - |
dc.identifier.bibliographicCitation | Journal of neuroscience research, 88(7). : 1537-1548, 2010 | - |
dc.identifier.eissn | 1097-4547 | - |
dc.relation.journalid | J003604012 | - |
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