Theranostics 2016; 6(12):2015-2027. doi:10.7150/thno.15993

Research Paper

Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1

Jenq-Lin Yang1, Wei-Yu Chen1, Yin-Ping Chen 1, Chao-Ying Kuo 1, Shang-Der Chen1,2,3,✉

1. Institute for Translation Research in Biomedicine;
2. Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung City 83301, Taiwan;
3. College of Medicine, Chang Gung University, 259 Wenhua 1st Road, Taoyuan City 33302, Taiwan

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.

Keywords: Glucagon-like peptide-1(GLP-1), Exendin-4, Oxidative DNA damage, Base excision repair (BER), Apurinic/apyrimidinic endonuclease 1 (APE1)

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How to cite this article:
Yang JL, Chen WY, Chen YP, Kuo CY, Chen SD. Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1. Theranostics 2016; 6(12):2015-2027. doi:10.7150/thno.15993. Available from http://www.thno.org/v06p2015.htm