Activation of AMPK is neuroprotective in the oxidative stress by advanced glycosylation end products in human neural stem cells

• Published in: Experimental cell research Vol. 359; no. 2; pp. 367 - 373
• Main Authors: Lin, Chien-Hung, Cheng, Yi-Chuan, Nicol, Christopher J., Lin, Kuan-Hung, Yen, Chia-Hui, Chiang, Ming-Chang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2017
• Subjects: AGEs; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Catalase - genetics; Catalase - metabolism; Cell Proliferation; Cells, Cultured; Enzyme Activation - drug effects; Gene Expression Regulation; Glutathione - metabolism; Glycation End Products, Advanced - antagonists & inhibitors; Glycation End Products, Advanced - pharmacology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HNSCs; Humans; Hypoglycemic Agents - pharmacology; Metformin; Metformin - pharmacology; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - enzymology; Oxidative stress; Oxidative Stress - drug effects; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Receptor for Advanced Glycation End Products - genetics; Receptor for Advanced Glycation End Products - metabolism; Signal Transduction; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Oxidative stress; AMPK; AGEs; Metformin; HNSCs
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2017.08.019

Advanced glycosylation end products (AGEs) formation is correlated with the pathogenesis of diabetic neuronal damage, but its links with oxidative stress are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). Once activated, AMPK regulates many pathways central to metabolism and energy balance including, glucose uptake, glycolysis and fatty acid oxidation. AMPK is also present in neurons, but its role remains unclear. Here, we show that AGE exposure decreases cell viability of human neural stem cells (hNSCs), and that the AMPK agonist metformin reverses this effect, via AMPK-dependent downregulation of RAGE levels. Importantly, hNSCs co-treated with metformin were significantly rescued from AGE-induced oxidative stress, as reflected by the normalization in levels of reactive oxygen species. In addition, compared to AGE-treated hNSCs, metformin co-treatment significantly reversed the activity and mRNA transcript level changes of SOD1/2 and Gpx. Furthermore, hNSCs exposed to AGEs had significantly lower mRNA levels among other components of normal cellular oxidative defenses (GSH, Catalase and HO-1), which were all rescued by co-treatment with metformin. This metformin-mediated protective effect on hNSCs for of both oxidative stress and oxidative defense genes by co-treatment with metformin was blocked by the addition of an AMPK antagonist (Compound C). These findings unveil the protective role of AMPK-dependent metformin signaling during AGE mediated oxidative stress in hNSCs, and suggests patients undergoing AGE-mediated neurodegeneration may benefit from the novel therapeutic use of metformin. •Metformin rescues cell growth and oxidative stress in AGE-treated hNSCs via AMPK.•Metformin increases SOD activity and genes in hNSCs exposed to AGEs.•Metformin increased Gpx activity and gene expression in AGE-treated hNSCs.•Metformin increased GSH levels, Catalase and HO-1 genes in AGEs-treated hNSCs.