Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells.

Abstract

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.

• Authors: Yazhou Li, David Tweedie, Mark P Mattson, Harold W Holloway, Nigel H Greig
• Journal: Journal of neurochemistry (J Neurochem) Vol. 113 Issue 6 Pg. 1621-31 (Jun 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20374430 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic Agents
• Butadienes
• Enzyme Inhibitors
• GLP1R protein, human
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Neuroprotective Agents
• Nitriles
• Oxidants
• Peptides
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Glucagon
• U 0126
• Venoms
• bcl-2-Associated X Protein
• Activating Transcription Factor 4
• Colforsin
• Glucagon-Like Peptide 1
• Oxidopamine
• Exenatide
• Hydrogen Peroxide
• Cyclic AMP
• Caspase 3
• Bromodeoxyuridine

Topics

• Activating Transcription Factor 4 (metabolism)
• Adrenergic Agents (toxicity)
• Apoptosis (drug effects)
• Bromodeoxyuridine (metabolism)
• Butadienes (pharmacology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, physiology)
• Colforsin (pharmacology)
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Exenatide
• Glucagon-Like Peptide 1 (pharmacology)
• Glucagon-Like Peptide-1 Receptor
• Humans
• Hydrogen Peroxide (toxicity)
• Hypoglycemic Agents (pharmacology)
• Neuroblastoma
• Neuroprotective Agents (pharmacology)
• Nitriles (pharmacology)
• Oxidants (toxicity)
• Oxidopamine (toxicity)
• Peptides (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Glucagon (genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Time Factors
• Transfection (methods)
• Venoms (pharmacology)
• bcl-2-Associated X Protein (metabolism)