title: Astrocyte-derived GDNF is a potent inhibitor of microglial activation.
abstract: 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.
authors.affiliation: CICS-UBI — Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: Sandra Moreira
authors.initials: SM
authors.lastname: Rocha
authors.forename: Ana Clara
authors.initials: AC
authors.lastname: Cristovão
authors.forename: Filipa Lopes
authors.initials: FL
authors.lastname: Campos
authors.forename: Carla Pais
authors.initials: CP
authors.lastname: Fonseca
authors.forename: Graça
authors.initials: G
authors.lastname: Baltazar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D029681:Arabidopsis Proteins / Q000378:metabolism; D001253:Astrocytes / Q000737:chemistry; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology*; D019751:Intramolecular Transferases / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D009414:Nerve Growth Factors; D010587:Phagocytosis / Q000187:drug effects; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D015054:Zymosan / Q000494:pharmacology
chemical_list: D029681:Arabidopsis Proteins; D019208:Brain-Derived Neurotrophic Factor; C522217:CDNF protein, human; D017077:Culture Media, Conditioned; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D015054:Zymosan; D019751:Intramolecular Transferases; C568454:marneral synthase, Arabidopsis