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Int. J. Mol. Sci. 2017, 18(3), 674; doi:10.3390/ijms18030674

ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition

1
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea
2
Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 570-749, Korea
3
College of Oriental Medicine, Wonkwang University, Iksan 570-749, Korea
4
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Received: 26 December 2016 / Revised: 11 March 2017 / Accepted: 16 March 2017 / Published: 21 March 2017
(This article belongs to the Special Issue Neuroprotective Strategies 2017)
View Full-Text   |   Download PDF [3308 KB, uploaded 21 March 2017]   |  

Abstract

Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. View Full-Text
Keywords: hypoglycemia; d-β-hydroxybutyrate; metformin; reactive oxygen species; extracellular signal-regulated kinase hypoglycemia; d-β-hydroxybutyrate; metformin; reactive oxygen species; extracellular signal-regulated kinase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lamichhane, S.; Bastola, T.; Pariyar, R.; Lee, E.-S.; Lee, H.-S.; Lee, D.H.; Seo, J. ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition. Int. J. Mol. Sci. 2017, 18, 674.

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