Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells.
Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (GLP-1R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 and the long-acting agonist exendin-4 stimulated cell proliferation and increased cell viability by 2-fold at 24 h at physiologically relevant concentrations. This GLP-1R-dependent action was mediated via the protein kinase A and phosphoinositide 3-kinase signaling pathways, with the MAPK pathway playing a minor role. GLP-1 and exendin-4 pretreatment dose-dependently protected SH-hGLP-1R#9 cells from hydrogen peroxide (H(2)O(2))- and 6-hydroxydopamine-induced cell death. This involved amelioration of elevated caspase 3 activity, down-regulation of pro-apoptotic Bax and up-regulation of anti-apoptotic Bcl-2 protein. In the presence of 6-hydroxydopamine, GLP-1's ability to lower caspase-3 activity was abolished with the phosphoinositide 3-kinase inhibitor, LY2940002, and partly reduced with the protein kinase A inhibitor, H89. Hence, GLP-1R mediated neurotrophic and anti-apoptotic actions co-contribute to the neuroprotective property of GLP-1 in neuronal cell cultures, and reinforce the potential therapeutic value of GLP-1R agonists in neurodegenerative disorders involving oxidative stress.
Li
Yazhou
Y
Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. liyaz@grc.nia.nih.gov
Tweedie
David
D
Mattson
Mark P
MP
Holloway
Harold W
HW
Greig
Nigel H
NH
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D018663:Adrenergic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D016877:Oxidants / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014688:Venoms / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D018663:Adrenergic Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D009570:Nitriles; D016877:Oxidants; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D018027:Receptors, Glucagon; C113580:U 0126; D014688:Venoms; D051028:bcl-2-Associated X Protein; D051701:Activating Transcription Factor 4; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D016627:Oxidopamine; D000077270:Exenatide; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D053148:Caspase 3; D001973:Bromodeoxyuridine