Interplay of Endoplasmic Reticulum Stress, Inflammation, Apoptosis, and Oxidative Stress in Corticosteroid-Induced Anxiety and Depression: Exploring Therapeutic Potential of Hydrogen Sulfide and Sertraline

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
May A. Azzam, Asmaa A. ElMonier*, Enas S. Gad and Mai A. Abd-Elmawla, 
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引用次数: 0

Abstract

Prolonged exposure to corticosteroids (CORTs) triggers depression and anxiety symptoms either endogenously or exogenously via stimulating endoplasmic reticulum stress (ERS). The study assessed the therapeutic implications of hydrogen sulfide (H2S) versus sertraline (SERT) in alleviating anxiety and depression induced by CORTs through the modulation of ERS and its inflammatory, oxidative, and apoptotic consequences. Rats were subdivided into four groups: control, CORT (20 mg/kg), NaHS (100 μmol/kg), and SERT (10 mg/kg) for 21 days. Behavioral and histological examinations of the cerebral cortex were performed. The levels of CHOP, GADD34, EIF2AK3, GRP78, caspase 3, and miR-146a were analyzed using qRT-PCR. The levels of CORTs, serotonin, BDNF, TNF-α, BCL2, NRF2, and ATF4 were measured using ELISA, whereas those of IL-1β and BAX were measured using immunohistochemical techniques. Total and phosphorylated PERK were assessed via western blotting, whereas GSH and MDA were assessed via a colorimetric assay. In the present study, CORTs upregulated the gene expression of CHOP, GADD34, EIF2AK3, GRP78, and Caspase 3, whereas it downregulated that of miR-146a. The levels of serotonin, BDNF, BCL2, GSH, and NRF2 were decreased, whereas those of ATF4, TNF-α, IL-1β, BAX, and MDA were elevated. On the contrary, NaHS and SERT reversed all the above-mentioned changes. H2S shows promise in counteracting anxiety and depression symptoms induced by CORTs by targeting ERS cascades, mitigating inflammation, oxidative insults, and apoptosis in the cerebral cortex. H2S elicits neuroprotective effects by targeting the miR-146a-3p/GRP78/CHOP/PERK/ATF4/GADD34 signaling pathway and regulating apoptotic markers BAX/BCL2 and inflammatory markers TNF-α and/IL-1β. Compared with SERT, H2S exhibited superior anxiolytic and antidepressive effects.

Abstract Image

内质网应激、炎症、凋亡和氧化应激在皮质类固醇诱导的焦虑和抑郁中的相互作用:硫化氢和舍曲林的治疗潜力探索
长期暴露于皮质类固醇(CORTs)通过刺激内质网应激(ERS)内源性或外源性触发抑郁和焦虑症状。该研究评估了硫化氢(H2S)与舍曲林(SERT)通过调节ERS及其炎症、氧化和凋亡后果来缓解CORTs诱导的焦虑和抑郁的治疗意义。将大鼠再分为对照组、CORT (20 mg/kg)组、NaHS (100 μmol/kg)组和SERT (10 mg/kg)组,持续21 d。进行大脑皮层行为学和组织学检查。采用qRT-PCR分析CHOP、GADD34、EIF2AK3、GRP78、caspase 3和miR-146a的水平。采用ELISA法检测各组血清中CORTs、血清素、BDNF、TNF-α、BCL2、NRF2和ATF4的水平,采用免疫组化技术检测各组血清中IL-1β和BAX的水平。总PERK和磷酸化PERK通过免疫印迹法评估,而GSH和MDA通过比色法评估。在本研究中,CORTs上调CHOP、GADD34、EIF2AK3、GRP78和Caspase 3的基因表达,而下调miR-146a的基因表达。血清素、BDNF、BCL2、GSH、NRF2水平降低,而ATF4、TNF-α、IL-1β、BAX、MDA水平升高。相反,NaHS和SERT逆转了上述所有变化。H2S有望通过靶向ERS级联,减轻大脑皮层的炎症、氧化损伤和凋亡,来对抗CORTs诱导的焦虑和抑郁症状。H2S通过靶向miR-146a-3p/GRP78/CHOP/PERK/ATF4/GADD34信号通路,调节凋亡标记物BAX/BCL2和炎症标记物TNF-α和/IL-1β,引发神经保护作用。与SERT相比,H2S表现出更强的抗焦虑和抗抑郁作用。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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