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

Da Yong Lee, Young J. Oh, Byung Kwan Jin

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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)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and by increasing production of TNF-α 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.

Original languageEnglish
Pages (from-to)98-110
Number of pages13
JournalGLIA
Volume51
Issue number2
DOIs
Publication statusPublished - 2005 Aug 1

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Dopaminergic Neurons
Microglia
Mitogen-Activated Protein Kinases
Thrombin
Neurons
p38 Mitogen-Activated Protein Kinases
Conditioned Culture Medium
Phosphotransferases
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Protein Kinase Inhibitors
Coculture Techniques
Interleukin-1
Parkinson Disease
Interleukin-6
Nitric Oxide
Cell Death

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: Dual roles of mitogen-activated protein kinase signaling pathways",
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)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and by increasing production of TNF-α 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.",
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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. / Lee, Da Yong; Oh, Young J.; Jin, Byung Kwan.

In: GLIA, Vol. 51, No. 2, 01.08.2005, p. 98-110.

Research output: Contribution to journalArticle

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