Sarawi Wedad S, Algarzae Norah K, Alharbi Nada M, Alhusaini Ahlam M, Akkam Layan M, Alsharidah Reem E, Alrasheed Latifah S, Attia Hala A, Hasan Iman H
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh, 11495, Saudi Arabia.
Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Sci Rep. 2025 Jul 1;15(1):21658. doi: 10.1038/s41598-025-06339-5.
Chronic stress, a common condition in modern life, is increasingly connected to a variety of medical concerns, including liver damage. Despite being one of the body's most resilient organs, the liver is yet susceptible to the harmful effects of chronic stress. This study aimed to investigate the therapeutic effects of fluoxetine and agomelatine on the liver after exposure to the chronic restraint stress (CRS) model in rats. Thirty-six male Sprague-Dawley rats were randomized into four groups: control, CRS + vehicle, CRS + fluoxetine, and CRS + agomelatine. Except for controls, all rats underwent CRS (2.5 h/day) for five weeks. During the last three weeks, groups received daily oral vehicle, fluoxetine, or agomelatine. Behavioral tests, forced swim test (FST) and sucrose preference test (SPT), were performed in the final week. Blood and liver samples were collected for biochemical and immunohistochemical analyses for liver enzymes, hepatic oxidative stress, and apoptotic and proliferative markers. The use of agomelatine for three consecutive weeks in CRS rats reversed immobility and climbing and slightly improved sucrose preference. No significant changes were detected in plasma liver transaminases compared to the control or treated groups. Nonetheless, agomelatine treatment significantly attenuated the oxidative stress induced by CRS, particularly in malondialdehyde (MDA) level (*P ≤ 0.05). The histological examination of liver tissues revealed fluoxetine and agomelatine mitigated CRS-induced cellular infiltration and nuclear hyperchromasia. Additionally, both drugs significantly reduced the upregulation of caspase-3 (***P ≤ 0.001) and proliferating cell nuclear antigen (PCNA, ***P ≤ 0.001) in CRS rats. This study revealed for the first time the potential therapeutic role of fluoxetine and agomelatine on the liver during the CRS depression model by controlling oxidative stress and hepatic regeneration.
慢性应激是现代生活中的常见状况，它与包括肝损伤在内的多种医学问题的关联日益紧密。尽管肝脏是人体最具韧性的器官之一，但它仍易受慢性应激的有害影响。本研究旨在探究氟西汀和阿戈美拉汀对大鼠慢性束缚应激（CRS）模型暴露后肝脏的治疗效果。将36只雄性斯普拉格-道利大鼠随机分为四组：对照组、CRS + 赋形剂组、CRS + 氟西汀组和CRS + 阿戈美拉汀组。除对照组外，所有大鼠均接受为期五周的CRS（每天2.5小时）。在最后三周，各实验组每日分别口服赋形剂、氟西汀或阿戈美拉汀。在最后一周进行行为测试，即强迫游泳试验（FST）和蔗糖偏好试验（SPT）。采集血液和肝脏样本，用于对肝酶、肝脏氧化应激以及凋亡和增殖标志物进行生化和免疫组化分析。在CRS大鼠中连续三周使用阿戈美拉汀可逆转不动和攀爬行为，并略微改善蔗糖偏好。与对照组或治疗组相比，血浆肝转氨酶未检测到显著变化。尽管如此，阿戈美拉汀治疗可显著减轻CRS诱导的氧化应激，尤其是丙二醛（MDA）水平（*P≤0.05）。肝组织的组织学检查显示，氟西汀和阿戈美拉汀可减轻CRS诱导的细胞浸润和核染色质增多。此外，两种药物均显著降低了CRS大鼠中caspase-3（***P≤0.001）和增殖细胞核抗原（PCNA，***P≤0.001）的上调。本研究首次揭示了氟西汀和阿戈美拉汀在CRS抑郁模型期间通过控制氧化应激和肝脏再生对肝脏的潜在治疗作用。
