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

Publication date: Available online 15 August 2017
Source:Experimental Cell Research
Author(s): Chien-Hung Lin, Yi-Chuan Cheng, Christopher J. Nicol, Kuan-Hung Lin, Chia-Hui Yen, Ming-Chang Chiang
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 ofSOD1/2 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.



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