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Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways.

Authors
Lee, DY; Oh, YJ; Jin, BK
Citation
Glia, 51(2):98-110, 2005
Journal Title
Glia
ISSN
0894-14911098-1136
Abstract
This study evaluated the role of thrombin-activated microglia in the neurodegeneration of mesencephalic cultures. Immunocytochemical and biochemical evidence indicated that in co-cultures consisting of rat cortical microglia and mesencephalic neurons, thrombin led to nonselective loss of mesencephalic neurons. Accompanying neurodegeneration, microglial activation was obvious, evidenced by expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and by increasing production of TNF-alpha and nitric oxide (NO). In mesencephalic neurons treated with conditioned media (CM) taken from thrombin-activated microglia, the number of dopaminergic neurons was significantly attenuated. The neurotoxicity of the CM was diminished when it was derived from microglia co-treated with thrombin and either an extracellular signal-regulated kinase 1/2 (ERK1/2) pathway inhibitor (PD98059) or a p38-mitogen-activated protein kinase (p38-MAPK) inhibitor (SB203580). Moreover, jun N-terminal kinase (JNK) and p38-MAPK were activated in mesencephalic neurons treated with CM of thrombin-activated microglia. Inhibition of JNK and p38-MAPK rescued the dopaminergic neurons. Collectively, these results indicate that thrombin-activated microglia induce neurodegeneration in cultured mesencephalic neurons and that the MAPKs actively participate in both microglial activation and neurodegeneration. The present data carefully suggest that microglial activation triggered by thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.
MeSH terms
AnimalsCell Death/drug effectsCell Death/physiologyCells, CulturedCoculture TechniquesCulture Media, Conditioned/pharmacologyCytokines/metabolismDopamine/metabolismEnzyme Inhibitors/pharmacologyGliosis/chemically inducedGliosis/metabolismGliosis/physiopathologyJNK Mitogen-Activated Protein Kinases/drug effectsJNK Mitogen-Activated Protein Kinases/metabolismMAP Kinase Signaling System/drug effectsMAP Kinase Signaling System/physiology*Mesencephalon/metabolism*Mesencephalon/pathologyMesencephalon/physiopathologyMicroglia/drug effectsMicroglia/metabolism*Mitogen-Activated Protein Kinase 3/drug effectsMitogen-Activated Protein Kinase 3/metabolismNerve Degeneration/chemically inducedNerve Degeneration/metabolism*Nerve Degeneration/physiopathologyNeurons/drug effectsNeurons/metabolism*Neurons/pathologyNitric Oxide/biosynthesisNitric Oxide Synthase/metabolismNitric Oxide Synthase Type IIParkinson Disease/metabolismParkinson Disease/physiopathologyRatsRats, Sprague-DawleyThrombin/pharmacology*Up-Regulation/drug effectsUp-Regulation/physiologyp38 Mitogen-Activated Protein Kinases/drug effectsp38 Mitogen-Activated Protein Kinases/metabolism
DOI
10.1002/glia.20190
PMID
15789435
Appears in Collections:
Journal Papers > Research Organization > Institute for Medical Sciences
AJOU Authors
진, 병관
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