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Enhancing the GLP‐1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells
Author(s) -
Li Yazhou,
Tweedie David,
Mattson Mark P.,
Holloway Harold W.,
Greig Nigel H.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06731.x
Subject(s) - neuroprotection , microbiology and biotechnology , signal transduction , biology , mapk/erk pathway , neurotrophin , sh sy5y , protein kinase a , kinase , agonist , protein kinase b , receptor , pharmacology , cell culture , neuroblastoma , biochemistry , genetics
J. Neurochem. (2010) 113 , 1621–1631. 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 caspse‐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.