GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures.
Heme oxygenase-1 (HO-1) has been strongly highlighted because of its induction in many cell types by toxic stimuli, including oxidative stress. The intense HO-1 immunostaining in the substantia nigra of Parkinson disease (PD) patients suggests its involvement in the pathogenesis of this neurodegenerative disease. In this work we investigated HO-1 expression in rat substantia nigra postnatal cell cultures under conditions mimicking dopamine toxicity and its modulation by glial cell line-derived neurotrophic factor (GDNF), a potent neuroprotective factor for dopaminergic neurons. In neuron-glia cultures, we found that H2O2, a product of dopamine metabolism, or l-3,4-dihydroxyphenylalanine (L-DOPA), the dopamine precursor used in the therapy of PD, induced a fast up-regulation of HO-1 mRNA and protein levels, followed by a secondary down-regulation. H2O2 and L-DOPA also increased HO-1 expression in astrocyte cultures, but with a delayed time course in H2O2-treated cultures. HO-1 expression was decreased in neuron-glia cultures under conditions under which GDNF up-regulation was observed. Because exogenously applied GDNF prevented HO-1 up-regulation in cultures treated with H2O2 or l-DOPA, and antibody neutralization of GDNF prevented the secondary HO-1 down-regulation observed in neuron-glia cultures, we propose that GDNF negatively modulates HO-1 expression induced by oxidative stress. To our knowledge, this is the first report showing the modulation of HO-1 expression by GDNF.
Saavedra
Ana
A
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Baltazar
Graça
G
Carvalho
Caetana M
CM
Duarte
Emília P
EP
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D015854:Up-Regulation
D000906:Antibodies; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007980:Levodopa; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1