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Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase.

Authors
Ishida, Y; Nagai, A; Kobayashi, S; Kim, SU
Citation
Journal of neuropathology and experimental neurology, 65(1):66-77, 2006
Journal Title
Journal of neuropathology and experimental neurology
ISSN
0022-30691554-6578
Abstract
In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1beta, IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.
MeSH terms
AgedAged, 80 and overAstrocytes/drug effectsAstrocytes/metabolism*Case-Control StudiesCell Survival/drug effectsCell Survival/physiologyCells, CulturedCytokines/metabolismDose-Response Relationship, DrugEnzyme-Linked Immunosorbent Assay/methodsFemaleGlial Fibrillary Acidic Protein/metabolismGlutathione Peroxidase/physiology*HumansImmunohistochemistry/methodsMaleNerve Growth Factors/metabolismNeurons/drug effectsNeurons/metabolismParkinson Disease/metabolismParkinson Disease/pathology*Prothrombin/metabolismRNA, Messenger/biosynthesisReceptor, PAR-1/classificationReceptor, PAR-1/geneticsReceptor, PAR-1/metabolism*Reverse Transcriptase Polymerase Chain Reaction/methodsTetrazolium Salts/diagnostic useThiazoles/diagnostic useThrombin/metabolismThrombin/pharmacologyTime FactorsUp-Regulation/drug effectsUp-Regulation/physiology*
PMID
16410750
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
AJOU Authors
김, 승업
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