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.

Highlights

  • Neurons in the central nervous system (CNS) regulate their intracellular pH via particular membrane proteins

  • Values are expressed as means ± SEM. #p < 0.05 vs. control group; *p < 0.05 vs. chronic unpredictable mild stress (CUMS) group (Fig. 3g, h). These results suggested that rho-associated kinase 2 (ROCK2) inhibition attenuated hippocampal neuronal apoptosis in the CUMS-induced animal model of depression

  • We first investigated the effects of ROCK2 inhibition in a CUMS-induced animal model of depression

Read more

Summary

Introduction

Neurons in the central nervous system (CNS) regulate their intracellular pH (pHi) via particular membrane proteins. Na+/H+ exchanger (NHE) is a primary membrane protein ubiquitously expressed with which neurons adjust their pHi to mediate DNA synthesis, cell volume, and protein function and degradation in the initiation of Official journal of the Cell Death Differentiation Association. Deng et al Cell Death and Disease (2019)10:370 enhances intestinal NHE activity via stimulation of the Gcoupled 5-HT1A and Gq/11-coupled 5-HT2 receptors[7]. Altered NHE1 function influences neuronal excitability and plays a role in epilepsy. Major depression is recognised as a chronic inflammatory neuropsychiatric disorder[8]. Rho-associated kinase (ROCK) plays an important role during the treatment of various diseases, including CNS disorders. ROCK has two isoforms, ROCK1 and ROCK2

Methods
Results
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.