Suppressing the Na+/H+ exchanger 1: a new sight to treat depression
Suppressing the Na+/H+ exchanger 1: a new sight to treat depression
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抑制Na/H交换体1：治疗抑郁症的新视角
DOI：
10.1038/s41419-019-1602-5
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发表时间：
2019-05-08
影响因子：
9
通讯作者：
Ma, Shiping
中科院分区：
文献类型：
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作者：
Deng, Xueyang;Ji, Zhouye;Ma, Shiping
Na+/H+交换体1（NHE 1）是细胞内pH（pHi）和细胞外pH（pHe）的重要调节因子，在多种生理和病理过程中起着重要作用。然而，NHE 1在抑郁症中的作用尚未报道。本研究旨在探讨NHE 1在抑郁症动物模型中的作用及其机制。我们的研究结果表明，通过法舒地尔（Fas）或黄芩苷（BA）抑制rho相关激酶2（ROCK 2）可显著减轻慢性不可预测的轻度应激（CHR）范式诱导的小鼠抑郁相关行为，如蔗糖偏好试验（SPT）中蔗糖消耗减少，旷场试验（OFT）中运动活动减少，悬尾试验（TST）和强迫游泳试验（FST）中不动时间延长。此外，ROCK 2抑制抑制NHE 1，钙蛋白酶1的激活，并减少神经元凋亡的抑郁症的EADS动物模型。接下来，我们使用脂多糖（LPS）攻击的抑郁症动物模型来诱导NHE 1激活。我们的结果表明，小鼠侧脑室注射1 μ l LPS（10 mg/ml），表现出抑郁样行为和NHE 1激活。NHE 1抑制剂Amiloride（Ami）可显著逆转LPS诱导的TST和FST中蔗糖消耗量的减少和不动时间的缩短。此外，Ami降低了LPS攻击小鼠海马中ROCK 2、NHE 1、calpain 1和caspase-3的表达，并增加了Bcl-1/Bax比值。AMI治疗也导致了抗抑郁作用，在CNS诱导的抑郁症动物模型。因此，抑制ROCK 2可能是一种神经保护策略，可以防止神经元凋亡，NHE 1可能是一个潜在的治疗抑郁症的目标。
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, calpainl, 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 mu l 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.