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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.
Glia 2005; 51(2):98-110GLIA

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.

Authors+Show Affiliations

Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15789435

Citation

Lee, Da Yong, et al. "Thrombin-activated Microglia Contribute to Death of Dopaminergic Neurons in Rat Mesencephalic Cultures: Dual Roles of Mitogen-activated Protein Kinase Signaling Pathways." Glia, vol. 51, no. 2, 2005, pp. 98-110.
Lee DY, Oh YJ, Jin BK. Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. Glia. 2005;51(2):98-110.
Lee, D. Y., Oh, Y. J., & Jin, B. K. (2005). Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. Glia, 51(2), pp. 98-110.
Lee DY, Oh YJ, Jin BK. Thrombin-activated Microglia Contribute to Death of Dopaminergic Neurons in Rat Mesencephalic Cultures: Dual Roles of Mitogen-activated Protein Kinase Signaling Pathways. Glia. 2005 Aug 1;51(2):98-110. PubMed PMID: 15789435.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. AU - Lee,Da Yong, AU - Oh,Young J, AU - Jin,Byung Kwan, PY - 2005/3/25/pubmed PY - 2005/8/27/medline PY - 2005/3/25/entrez SP - 98 EP - 110 JF - Glia JO - Glia VL - 51 IS - 2 N2 - 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. SN - 0894-1491 UR - https://www.unboundmedicine.com/medline/citation/15789435/Thrombin_activated_microglia_contribute_to_death_of_dopaminergic_neurons_in_rat_mesencephalic_cultures:_dual_roles_of_mitogen_activated_protein_kinase_signaling_pathways_ L2 - https://doi.org/10.1002/glia.20190 DB - PRIME DP - Unbound Medicine ER -