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Cell Death Dis. 2019 May 8;10(5):370. doi: 10.1038/s41419-019-1602-5.

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

Deng X1,2, Ji Z1, Xu B1, Guo L1, Xu L, Qin T1, Feng L3, Ma Z1, Fu Q1, Qu R4, Quo Q5, Ma S6,7.

Author information

1
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 210009, Nanjing, China.
2
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 210009, Nanjing, China.
3
School of Traditional Chinese Pharmacy, China Pharmaceutical University, 211198, Nanjing, Jiangsu, China.
4
Department of Pharmacology of Traditional Chinese Medical Formulae, Nanjing University of Traditional Chinese Medicine, 210029, Nanjing, China.
5
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 210009, Nanjing, China. anticancer_drug@163.com.
6
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 210009, Nanjing, China. spma@cpu.edu.cn.
7
Qinba Traditional Chinese Medicine Resources Research and Development Center, AnKang University, 725000, AnKang, PR China. spma@cpu.edu.cn.

Abstract

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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