Selective injury to dopaminergic neurons up-regulates GDNF in substantia nigra postnatal cell cultures: role of neuron-glia crosstalk.
The effect of selective injury to dopaminergic neurons on the expression of glial cell line-derived neurotrophic factor (GDNF) was examined in substantia nigra cell cultures. H(2)O(2), mimicking increased oxidative stress, or l-DOPA, the main symptomatic treatment for Parkinson's disease, increased GDNF mRNA and protein levels in a time-dependent mode in neuron-glia mixed cultures. The concentration dependence indicated that mild, but not extensive, injury induced GDNF up-regulation. GDNF neutralization with an antibody decreased dopaminergic cell viability in H(2)O(2)-treated cultures, showing that up-regulation of GDNF was protecting dopaminergic neurons. Neither H(2)O(2) nor l-DOPA directly affected GDNF expression in astrocyte cultures, but conditioned media from challenged mixed cultures increased GDNF mRNA and protein levels in astrocyte cultures, indicating that GDNF up-regulation was mediated by neuronal factors. Since pretreatment with 6-OHDA completely abolished H(2)O(2)-induced GDNF up-regulation, we propose that GDNF up-regulation is triggered by failing dopaminergic neurons that signal astrocytes to increase GDNF expression.
Saavedra
Ana
A
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Baltazar
Graça
G
Santos
Paulo
P
Carvalho
Caetana M
CM
Duarte
Emília P
EP
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity; D007980:Levodopa / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013378:Substantia Nigra / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D013565:Sympatholytics / Q000494:pharmacology
D000906:Antibodies; D015259:Dopamine Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D013565:Sympatholytics; D007980:Levodopa; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D004298:Dopamine