Department of Neurology, Affiliated Center Hospital of Shenzhen Longhua New District, Guangdong Medical University, Shenzhen, Guangdong, P. R. China; Institute of Neuroscience, Medical College, University of South China, Hengyang, Hunan, P. R. China; Department of Neurology, Nanhua Affiliated Hospital, University of South China, Hengyang, Hunan, P. R. China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, Hunan, PR China.
Int J Neuropsychopharmacol. 2017 Nov 1;20(11):867-876. doi: 10.1093/ijnp/pyx030.
Hydrogen sulfide (H2S) is a crucial signaling molecule with a wide range of physiological functions. Previously, we confirmed that stress-induced depression is accompanied with disturbance of H2S generation in hippocampus. The present work attempted to investigate the inhibitory effect of H2S on chronic unpredictable mild stress-induced depressive-like behaviors and the underlying mechanism.
We established the rat model of chronic unpredictable mild stress to simulate depression. Open field test, forced swim test, and tail suspension test were used to assess depressive-like behaviors. The expression of Sirt-1 and three marked proteins related to endoplasmic reticulum stress (GRP-78, CHOP, and cleaved caspase-12) were detected by western blot.
We found that chronic unpredictable mild stress-exposed rats exhibit depression-like behavior responses, including significantly increased immobility time in the forced swim test and tail suspension test, and decreased climbing time and swimming time in the forced swim test. In parallel, chronic unpredictable mild stress-exposed rats showed elevated levels of hippocampal endoplasmic reticulum stress and reduced levels of Sirt-1. However, NaHS (a donor of H2S) not only alleviated chronic unpredictable mild stress-induced depressive-like behaviors and hippocampal endoplasmic reticulum stress, but it also increased the expression of hippocampal Sirt-1 in chronic unpredictable mild stress-exposed rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the protective effects of H2S against chronic unpredictable mild stress-induced depression-like behaviors and hippocampal endoplasmic reticulum stress.
These results demonstrated that H2S has an antidepressant potential, and the underlying mechanism is involved in the inhibition of hippocampal endoplasmic reticulum stress by upregulation of Sirt-1 in hippocampus. These findings identify H2S as a novel therapeutic target for depression.
硫化氢（H2S）是一种重要的信号分子，具有广泛的生理功能。先前我们证实，应激诱导的抑郁症伴随着海马中 H2S 生成的紊乱。本研究旨在探讨 H2S 对慢性不可预测轻度应激诱导的抑郁样行为的抑制作用及其潜在机制。
我们建立了慢性不可预测轻度应激大鼠模型来模拟抑郁症。利用旷场试验、强迫游泳试验和悬尾试验评估抑郁样行为。采用 Western blot 检测 Sirt-1 表达和内质网应激相关的 3 个标志性蛋白（GRP-78、CHOP 和 cleaved caspase-12）的表达。
我们发现，慢性不可预测轻度应激暴露的大鼠表现出抑郁样行为反应，包括强迫游泳试验和悬尾试验中不动时间显著增加，强迫游泳试验中攀爬时间和游泳时间减少。同时，慢性不可预测轻度应激暴露的大鼠海马内质网应激水平升高，Sirt-1 水平降低。然而，NaHS（H2S 的供体）不仅缓解了慢性不可预测轻度应激诱导的抑郁样行为和海马内质网应激，还增加了慢性不可预测轻度应激暴露大鼠海马 Sirt-1 的表达。此外，Sirtinol（Sirt-1 抑制剂）逆转了 H2S 对慢性不可预测轻度应激诱导的抑郁样行为和海马内质网应激的保护作用。
这些结果表明 H2S 具有抗抑郁作用，其潜在机制涉及通过上调海马 Sirt-1 抑制海马内质网应激。这些发现确定 H2S 是一种治疗抑郁症的新靶点。
