PMID- 22579772 OWN - NLM STAT- MEDLINE DCOM- 20121129 LR - 20120709 IS - 1095-953X (Electronic) IS - 0969-9961 (Linking) VI - 47 IP - 3 DP - 2012 Sep TI - Astrocyte-derived GDNF is a potent inhibitor of microglial activation. PG - 407-15 LID - 10.1016/j.nbd.2012.04.014 [doi] AB - Neuroinflammation is recognized as a major factor in Parkinson's disease (PD) pathogenesis and increasing evidence propose that microglia is the main source of inflammation contributing to the dopaminergic degeneration observed in PD. Several studies suggest that astrocytes could act as physiological regulators preventing excessive microglia responses. However, little is known regarding how astrocytes modulate microglial activation. In the present study, using Zymosan A-stimulated midbrain microglia cultures, we showed that astrocytes secrete factors capable of modulating microglial activation, namely its phagocytic activity and the production of reactive oxygen species since both parameters were highly diminished in cells incubated with astrocytes conditioned media (ACM). Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF) and brain-derived neurotrophic factor (BDNF), known to have a neuroprotective role in the nigrostriatal system, are among the candidates to be astrocyte-secreted molecules involved in the modulation of microglial activation. The effect of ACM on Zymosan A-induced microglial activation was abolished when the GDNF present in the ACM was abrogated using a specific antibody, but not when ACM was neutralized with anti-CDNF, anti-BDNF or with a heat-inactivated GDNF antibody. In addition, media conditioned by astrocytes silenced for GDNF were not able to prevent microglial activation, whereas supplementation of non-conditioned media with GDNF prevented the activation of microglia evoked by Zymosan A. Taken together, these results indicate that astrocyte-derived GDNF plays a major contribution to the control of midbrain microglial activation, suggesting that GDNF can protect from neurodegeneration through the inhibition of neuroinflammation. CI - Copyright (c) 2012 Elsevier Inc. All rights reserved. FAU - Rocha, Sandra Moreira AU - Rocha SM AD - CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilha, Portugal. FAU - Cristovao, Ana Clara AU - Cristovao AC FAU - Campos, Filipa Lopes AU - Campos FL FAU - Fonseca, Carla Pais AU - Fonseca CP FAU - Baltazar, Graca AU - Baltazar G LA - eng PT - Journal Article DEP - 20120503 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Arabidopsis Proteins) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (CDNF protein, human) RN - 0 (Culture Media, Conditioned) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Nerve Growth Factors) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - 9010-72-4 (Zymosan) RN - EC 5.4.- (Intramolecular Transferases) RN - EC 5.4.- (marneral synthase, Arabidopsis) SB - IM MH - Animals MH - Animals, Newborn MH - Arabidopsis Proteins/metabolism MH - Astrocytes/chemistry MH - Brain-Derived Neurotrophic Factor/metabolism/pharmacology MH - Cells, Cultured MH - Culture Media, Conditioned/pharmacology MH - Drug Interactions MH - Enzyme-Linked Immunosorbent Assay/methods MH - Gene Expression Regulation/drug effects MH - Glial Cell Line-Derived Neurotrophic Factor/*metabolism/*pharmacology MH - Intramolecular Transferases/metabolism MH - Mesencephalon/cytology MH - Microglia/*drug effects/*metabolism MH - Nerve Growth Factors MH - Phagocytosis/drug effects MH - RNA, Messenger MH - RNA, Small Interfering/genetics/metabolism MH - Rats MH - Rats, Wistar MH - Reactive Oxygen Species/metabolism MH - Transfection MH - Zymosan/pharmacology EDAT- 2012/05/15 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/05/15 06:00 PHST- 2011/06/08 00:00 [received] PHST- 2012/03/29 00:00 [revised] PHST- 2012/04/26 00:00 [accepted] PHST- 2012/05/15 06:00 [entrez] PHST- 2012/05/15 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - S0969-9961(12)00160-X [pii] AID - 10.1016/j.nbd.2012.04.014 [doi] PST - ppublish SO - Neurobiol Dis. 2012 Sep;47(3):407-15. doi: 10.1016/j.nbd.2012.04.014. Epub 2012 May 3.