Azzam May A, ElMonier Asmaa A, Gad Enas S, Abd-Elmawla Mai A
Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
ACS Chem Neurosci. 2025 Apr 2;16(7):1361-1376. doi: 10.1021/acschemneuro.5c00057. Epub 2025 Mar 24.
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 (HS) 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. HS 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. HS 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, HS exhibited superior anxiolytic and antidepressive effects.
长期暴露于皮质类固醇（CORTs）会通过刺激内质网应激（ERS）内源性或外源性地引发抑郁和焦虑症状。该研究评估了硫化氢（HS）与舍曲林（SERT）在通过调节ERS及其炎症、氧化和凋亡后果来减轻CORTs诱导的焦虑和抑郁方面的治疗意义。将大鼠分为四组：对照组、CORT（20 mg/kg）组、NaHS（100 μmol/kg）组和SERT（10 mg/kg）组，持续21天。对大脑皮层进行行为学和组织学检查。使用qRT-PCR分析CHOP、GADD34、EIF2AK3、GRP78、半胱天冬酶3和miR-146a的水平。使用ELISA测量CORTs、血清素、脑源性神经营养因子（BDNF）、肿瘤坏死因子-α（TNF-α）、B细胞淋巴瘤2（BCL2）、核因子E2相关因子2（NRF2）和活化转录因子4（ATF4）的水平，而使用免疫组织化学技术测量白细胞介素-1β（IL-1β）和凋亡相关蛋白（BAX）的水平。通过蛋白质免疫印迹法评估总PERK和磷酸化PERK，而通过比色法评估谷胱甘肽（GSH）和丙二醛（MDA）。在本研究中，CORTs上调了CHOP、GADD34、EIF2AK3、GRP78和半胱天冬酶3的基因表达，而下调了miR-146a的基因表达。血清素、BDNF、BCL2、GSH和NRF2的水平降低，而ATF4、TNF-α、IL-1β、BAX和MDA的水平升高。相反，NaHS和SERT逆转了上述所有变化。HS通过靶向ERS级联反应、减轻大脑皮层的炎症、氧化损伤和凋亡，在对抗CORTs诱导的焦虑和抑郁症状方面显示出前景。HS通过靶向miR-146a-3p/GRP78/CHOP/PERK/ATF4/GADD34信号通路并调节凋亡标志物BAX/BCL2以及炎症标志物TNF-α和/或IL-1β发挥神经保护作用。与SERT相比，HS表现出更强的抗焦虑和抗抑郁作用。
