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Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression

Na(+)/H(+) exchanger 1 (NHE1), an important regulator of intracellular pH (pHi) and extracellular pH (pHe), plays a crucial role in various physiological and pathological processes. However, the role of NHE1 in depression has not yet been reported. This study was designed to investigate the role of...

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Autores principales: Deng, Xueyang, Ji, Zhouye, Xu, Bingru, Guo, Liting, Xu, Lixing, Qin, Tingting, Feng, Liang, Ma, Zhanqiang, Fu, Qiang, Qu, Rong, Quo, Qinglong, Ma, Shiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506522/
https://www.ncbi.nlm.nih.gov/pubmed/31068571
http://dx.doi.org/10.1038/s41419-019-1602-5
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author Deng, Xueyang
Ji, Zhouye
Xu, Bingru
Guo, Liting
Xu, Lixing
Qin, Tingting
Feng, Liang
Ma, Zhanqiang
Fu, Qiang
Qu, Rong
Quo, Qinglong
Ma, Shiping
author_facet Deng, Xueyang
Ji, Zhouye
Xu, Bingru
Guo, Liting
Xu, Lixing
Qin, Tingting
Feng, Liang
Ma, Zhanqiang
Fu, Qiang
Qu, Rong
Quo, Qinglong
Ma, Shiping
author_sort Deng, Xueyang
collection PubMed
description Na(+)/H(+) exchanger 1 (NHE1), an important regulator of intracellular pH (pHi) and extracellular pH (pHe), plays a crucial role in various physiological and pathological processes. However, the role of NHE1 in depression has not yet been reported. This study was designed to investigate the role of NHE1 in the animal model of depression and explore the underlying mechanisms. Our results showed that inhibition of rho-associated kinase 2 (ROCK2) by fasudil (Fas) or baicalin (BA) significantly alleviated chronic unpredictable mild stress (CUMS) paradigm-induced depression-related behaviours in mice, as shown by decreased sucrose consumption in sucrose preference test (SPT), reduced locomotor activity in the open field test (OFT), and increased immobility time in the tail suspension test (TST) and forced swimming test (FST). Furthermore, ROCK2 inhibition inhibited the activation of NHE1, calpain1, and reduced neuronal apoptosis in the CUMS animal model of depression. Next, we used the lipopolysaccharide (LPS)-challenged animal model of depression to induce NHE1 activation. Our results revealed that mice subjected to 1 μl LPS (10 mg/ml) injection intracerebroventricularly (i.c.v.) showed depressive-like behaviours and NHE1 activation. Amiloride (Ami), an NHE1 inhibitor, significantly reversed the decrease in sucrose consumption and reduction in immobility time in the TST and FST induced by LPS challenge. Furthermore, Ami decreased the expression of ROCK2, NHE1, calpain1, and caspase-3 and increased the Bcl-1/Bax ratio in the hippocampus of LPS-challenged mice. Ami treatment also led to antidepressive effects in the CUMS-induced animal model of depression. Thus ROCK2 inhibition could be proposed as a neuroprotective strategy against neuronal apoptosis, and NHE1 might be a potential therapeutic target in depression.
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spelling pubmed-65065222019-05-09 Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression Deng, Xueyang Ji, Zhouye Xu, Bingru Guo, Liting Xu, Lixing Qin, Tingting Feng, Liang Ma, Zhanqiang Fu, Qiang Qu, Rong Quo, Qinglong Ma, Shiping Cell Death Dis Article Na(+)/H(+) exchanger 1 (NHE1), an important regulator of intracellular pH (pHi) and extracellular pH (pHe), plays a crucial role in various physiological and pathological processes. However, the role of NHE1 in depression has not yet been reported. This study was designed to investigate the role of NHE1 in the animal model of depression and explore the underlying mechanisms. Our results showed that inhibition of rho-associated kinase 2 (ROCK2) by fasudil (Fas) or baicalin (BA) significantly alleviated chronic unpredictable mild stress (CUMS) paradigm-induced depression-related behaviours in mice, as shown by decreased sucrose consumption in sucrose preference test (SPT), reduced locomotor activity in the open field test (OFT), and increased immobility time in the tail suspension test (TST) and forced swimming test (FST). Furthermore, ROCK2 inhibition inhibited the activation of NHE1, calpain1, and reduced neuronal apoptosis in the CUMS animal model of depression. Next, we used the lipopolysaccharide (LPS)-challenged animal model of depression to induce NHE1 activation. Our results revealed that mice subjected to 1 μl LPS (10 mg/ml) injection intracerebroventricularly (i.c.v.) showed depressive-like behaviours and NHE1 activation. Amiloride (Ami), an NHE1 inhibitor, significantly reversed the decrease in sucrose consumption and reduction in immobility time in the TST and FST induced by LPS challenge. Furthermore, Ami decreased the expression of ROCK2, NHE1, calpain1, and caspase-3 and increased the Bcl-1/Bax ratio in the hippocampus of LPS-challenged mice. Ami treatment also led to antidepressive effects in the CUMS-induced animal model of depression. Thus ROCK2 inhibition could be proposed as a neuroprotective strategy against neuronal apoptosis, and NHE1 might be a potential therapeutic target in depression. Nature Publishing Group UK 2019-05-08 /pmc/articles/PMC6506522/ /pubmed/31068571 http://dx.doi.org/10.1038/s41419-019-1602-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Deng, Xueyang
Ji, Zhouye
Xu, Bingru
Guo, Liting
Xu, Lixing
Qin, Tingting
Feng, Liang
Ma, Zhanqiang
Fu, Qiang
Qu, Rong
Quo, Qinglong
Ma, Shiping
Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression
title Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression
title_full Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression
title_fullStr Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression
title_full_unstemmed Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression
title_short Suppressing the Na(+)/H(+) exchanger 1: a new sight to treat depression
title_sort suppressing the na(+)/h(+) exchanger 1: a new sight to treat depression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506522/
https://www.ncbi.nlm.nih.gov/pubmed/31068571
http://dx.doi.org/10.1038/s41419-019-1602-5
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