Astrocyte-secreted GDNF and glutathione antioxidant system protect neurons against 6OHDA cytotoxicity

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DOIResolve DOI: http://doi.org/10.1016/j.nbd.2008.11.016
AuthorSearch for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for:
TypeArticle
Journal titleNeurobiology of Disease
Volume33
Issue3
Pages405414; # of pages: 10
SubjectNeuroprotection; Neuro-regeneration; Neurotrophic factor; Signal transduction; Thiol antioxidant; Coculture; Viral vectors; Lentiviral vector; Oxidative stress; Gene therapy; administration & dosage; adverse effects; Analysis of Variance; Animals; antagonists & inhibitors; Antioxidants; Astrocytes; Blotting,Western; Brain; Buthionine Sulfoximine; Canada; cell; Cell Survival; CELLS; Coculture Techniques; complex; COMPLEXES; COMPONENT; COMPONENTS; Cytomegalovirus; drug effects; GENE; Gene Expression; Glial Cell Line-Derived Neurotrophic Factor; Glial Fibrillary Acidic Protein; Glutathione; Human; Humans; Immunohistochemistry; In Vitro; MECHANISMS; metabolism; Mice; MODEL; MOLECULAR; Neurons; Oxidopamine; PATHWAY; PATHWAYS; physiology; Polymerase Chain Reaction; PROTECTION; protein; secretion; Signal Transduction; SYSTEM; SYSTEMS; toxicity; Transfection
AbstractIn recent years, GDNF has emerged as a protective and restorative agent in several models of neurodegeneration; however, the exact molecular mechanisms responsible for these effects are not yet fully understood. Here we examined the effects of astrocytes secreting GDNF on neurons subjected to 6OHDA toxicity using in vitro neuron-astroglia co-cultures. Astrocytes were transduced with lentiviral vectors carrying the GDNF gene under the control of either human glial fibrillary acidic protein or cytomegalovirus promoters. The overexpression of GDNF, regardless of the promoter employed, had no obvious adverse effects on astroglia and the engineered cells stably produced and secreted GDNF for extended periods of time (≥3 weeks). These astrocytes very effectively protected neurons against 6OHDA, in both mouse and human co-culture systems. The neuroprotective effects were mediated not only by GDNF, but also by the antioxidant GSH since its depletion reduced the level of GDNF protection. Furthermore, neurons and astrocytes expressed different components of GDNF signaling complex, suggesting that they might utilize separate pathways to mediate autocrine and paracrine effects of GDNF.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences
Peer reviewedYes
NRC numberSANDHU2009
NPARC number15465376
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Record identifier2d67d98a-3db3-4454-a67c-6f1fb6e3df4e
Record created2010-08-16
Record modified2016-05-09
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