Cargando…

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

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 cytoto...

Descripción completa

Detalles Bibliográficos
Autores principales: Lamichhane, Santosh, Bastola, Tonking, Pariyar, Ramesh, Lee, Eun-Sol, Lee, Ho-Sub, Lee, Dae Ho, Seo, Jungwon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372684/
https://www.ncbi.nlm.nih.gov/pubmed/28335557
http://dx.doi.org/10.3390/ijms18030674
_version_ 1782518671617294336
author Lamichhane, Santosh
Bastola, Tonking
Pariyar, Ramesh
Lee, Eun-Sol
Lee, Ho-Sub
Lee, Dae Ho
Seo, Jungwon
author_facet Lamichhane, Santosh
Bastola, Tonking
Pariyar, Ramesh
Lee, Eun-Sol
Lee, Ho-Sub
Lee, Dae Ho
Seo, Jungwon
author_sort Lamichhane, Santosh
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5372684
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-53726842017-04-10 ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition Lamichhane, Santosh Bastola, Tonking Pariyar, Ramesh Lee, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Seo, Jungwon Int J Mol Sci Article 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. MDPI 2017-03-21 /pmc/articles/PMC5372684/ /pubmed/28335557 http://dx.doi.org/10.3390/ijms18030674 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lamichhane, Santosh
Bastola, Tonking
Pariyar, Ramesh
Lee, Eun-Sol
Lee, Ho-Sub
Lee, Dae Ho
Seo, Jungwon
ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
title ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
title_full ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
title_fullStr ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
title_full_unstemmed ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
title_short ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
title_sort ros production and erk activity are involved in the effects of d-β-hydroxybutyrate and metformin in a glucose deficient condition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372684/
https://www.ncbi.nlm.nih.gov/pubmed/28335557
http://dx.doi.org/10.3390/ijms18030674
work_keys_str_mv AT lamichhanesantosh rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition
AT bastolatonking rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition
AT pariyarramesh rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition
AT leeeunsol rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition
AT leehosub rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition
AT leedaeho rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition
AT seojungwon rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition