Fluoxetine and agomelatine mitigate anhedonic and hepatic changes in chronic restraint stress rat model

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.