半胱硫氨酸-β-合成酶衍生的硫化氢通过调节神经炎症参与糖皮质激素诱导的大鼠抑郁样行为

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-09-11 DOI:10.1016/j.brainresbull.2025.111549

Ying Zhao , Shi-Yi Ye , Long Li , Yi-Heng Li , Jin-Qiong Zhan , Li-Li Zheng , Yuan-Jian Yang , Bo Wei , Shu-Zhen Jiang , Xiao-Yan Cheng

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引用次数: 0

摘要

背景：长期使用糖皮质激素（GCs）可能导致抑郁不良反应。硫化氢（H2S）与抑郁症的病理生理有关，并具有调节神经炎症的能力，这是抑郁症发病机制的基础。本研究的目的是在大鼠模型中研究H2S信号是否有助于地塞米松（DEX）诱导的抑郁。方法大鼠皮下注射DEX(5 mg/kg)，每日1次，连续28 d。采用社会互动测验（SIT）、蔗糖偏好测验（SPT）、野外开放测验（OFT）和强迫游泳测验（FST）对实验对象的行为表现进行测试。采用免疫印迹法和免疫荧光法检测胱硫氨酸-β-合成酶（CBS）和诱导型一氧化氮合成酶（iNOS）的表达。采用酶联免疫吸附试验（ELISA）试剂盒检测细胞因子水平。采用H.E.染色法观察大鼠海马CA1区神经元形态学变化。结果我们发现，慢性DEX治疗大鼠出现明显的抑郁样行为，且DEX治疗大鼠海马中H2S和CBS（大脑中主要的H2S生成酶）水平显著降低。CBS的过表达增加了海马中H2S和CBS蛋白的水平，并减轻了dex处理大鼠的抑郁样行为，而抑制CBS活性则消除了CBS升高的有益作用。机制上，慢性右美托芬可降低大鼠抗炎细胞因子IL-10和TGF-β水平，升高促炎细胞因子IL-1β和TNF-α水平，引起海马神经元损伤，而CBS过表达逆转了右美托芬治疗引起的这些变化。此外，CBS过表达也恢复了dex处理大鼠海马中iNOS蛋白水平的升高，iNOS是小胶质细胞向M1表型极化以产生促炎作用的标志。结论cbs源性H2S参与糖皮质激素诱导的大鼠抑郁样行为，H2S信号通路可能参与神经炎症的调节。

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Cystathionine-β-synthase-derived hydrogen sulfide contributes to glucocorticoid-induced depressive-like behaviors in rats by modulating neuroinflammation

Background

Long-term treatment of glucocorticoids (GCs) may lead to depressive adverse effect. Hydrogen sulfide (H₂S) is implicated in the pathophysiology of depression and has an ability to modulate neuroinflammatory, which underlies the pathogenesis of depression. The aim of this study was to investigate whether H₂S signaling contributed to dexamethasone (DEX)-induced depression in a rat model.

Methods

Rats were subcutaneously injected with DEX (5 mg/kg) once daily for 28 days. The behavioral performances were examined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). The expressions of cystathionine-β-synthase (CBS) and inducible nitric oxide synthase (iNOS) were measured by western blotting and immunofluorescence assay. Cytokine levels were examined by enzyme-linked immunosorbent assay (ELISA) kits. The morphological changes of neurons in rat hippocampal CA1 region were observed using H.E. staining.

Results

We found that chronic DEX treatment caused obvious depressive-like behaviors in rats, and the levels of H₂S and CBS, the predominant H₂S-producing enzyme in the brain, were significantly reduced in the hippocampus of DEX-treated rats. Overexpression of CBS increased the levels of H₂S and CBS protein in the hippocampus and attenuated the depressive-like behaviors in DEX-treated rats, whereas inhibition of CBS activity abolished the beneficial effects of CBS elevation. Mechanismly, chronic DEX treatment reduced the levels of anti-inflammatory cytokines IL-10 and TGF-β, increased the levels of pro-inflammatory cytokines IL-1β and TNF-α, and caused neuronal damage in the hippocampus of rats, while CBS overexpression reversed these changes caused by DEX treatment. Furthermore, the increased protein level of iNOS, a marker of microglia polarizing to M1 phenotype to produce pro-inflammatory effects, in the hippocampus of DEX-treated rats was also restored by CBS overexpression.

Conclusion

These results indicate that CBS-derived H₂S contributes to glucocorticoid-induced depressive-like behaviors in rats, and the effects of H₂S signaling might involve the regulation of neuroinflammation.

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.