title: Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1.
abstract: Glucagon-like peptide-1 (GLP-1) is an intestinal-secreted incretin that increases cellular glucose up-take to decrease blood sugar. Recent studies, however, suggest that the function of GLP-1 is not only to decrease blood sugar, but also acts as a neurotrophic factor that plays a role in neuronal survival, neurite outgrowth, and protects synaptic plasticity and memory formation from effects of β-amyloid. Oxidative DNA damage occurs during normal neuron-activity and in many neurological diseases. Our study describes how GLP-1 affected the ability of neurons to ameliorate oxidative DNA damage. We show that activation of GLP-1 receptor (GLP-1R) protect cortical neurons from menadione induced oxidative DNA damage via a signaling pathway involving enhanced DNA repair. GLP-1 stimulates DNA repair by activating the cyclic AMP response element binding protein (CREB) which, consequently, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair (BER) pathway. In this study, APE1 expression was down-regulated as a consequence phosphatidylinositol-3 kinase (PI3K) suppression by the inhibitor LY294002, but not by the suppression of MEK activity. Ischemic stroke is typically caused by overwhelming oxidative-stress in brain cells. Administration of exentin-4, an analogue of GLP-1, efficiently enhanced DNA repair in brain cells of ischemic stroke rats. Our study suggests that a new function of GLP-1 is to elevate DNA repair by inducing the expression of the DNA repair protein APE1.
authors.affiliation: Institute for Translation Research in Biomedicine.
authors.forename: Jenq-Lin
authors.initials: JL
authors.lastname: Yang
authors.affiliation: Institute for Translation Research in Biomedicine.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Institute for Translation Research in Biomedicine.
authors.forename: Yin-Ping
authors.initials: YP
authors.lastname: Chen
authors.affiliation: Institute for Translation Research in Biomedicine.
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Institute for Translation Research in Biomedicine;; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung City 83301, Taiwan;; College of Medicine, Chang Gung University, 259 Wenhua 1st Road, Taoyuan City 33302, Taiwan.
authors.forename: Shang-Der
authors.initials: SD
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D024483:Vitamin K 3 / Q000633:toxicity
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D009153:Mutagens; D024483:Vitamin K 3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: Apurinic/apyrimidinic endonuclease 1 (APE1); Base excision repair (BER); Exendin-4; Glucagon-like peptide-1(GLP-1); Oxidative DNA damage