Effect of vortioxetine and fluoxetine on immunohistochemical expression of Caspase-8, RANKL, and IL-6 in testicular tissue in an experimental depression model

The main symptoms of depression, a chronic mental illness, include sadness, low self-esteem, and a diminished sense of enjoyment in life. Many factors have been suggested to be associated with depression, one of which is low testosterone in men. The serotonin reuptake inhibitor fluoxetine (FLU), used to treat depression, has been reported to potentially have detrimental effects on spermatogenesis in rats after long-term use. The multimodal antidepressant vortioxetine (VTX) offers new promise for the treatment of depression. The chronic unpredictable mild stress (CUMS) model is widely known as an experimental paradigm used to study depression-like behaviors in rodents. Stress leads to various neurochemical and immune changes, affecting multiple organs. Our study aims to examine the histopathological findings in testicular tissue induced by CUMS and the immunohistochemical expression of Cas-8, IL-6, and RANKL using a depression model in rats. Rats were split into 4 groups of 7 animals each at random. Group 1 (control) did not experience any stress. Group 2 (CUMS) was exposed to chronic, unpredictable mild stress using a specific procedure. Group 3 (CUMS+VTX) and Group 4 (CUMS+FLU) underwent CUMS and received intraperitoneal drug treatment at a dose of 10 mg/kg during the final three weeks of the study. The rat testicles collected during necropsy were evaluated histopathologically and immunohistochemically for Cas-8, IL-6, and RANKL expressions using a light microscope. In Group 1, histological analysis showed normal tissue architecture in the testicles and epididymis. In Group 2, there was significant depletion of spermatozoa in the seminiferous tubules and empty tubules in the epididymis. In Groups 3 and 4, FLU and VTX treatment led to improvements in the testicles. Cas-8, RANKL, and IL-6 immunohistochemistry revealed increased expression in Group 2, primarily in interstitial cells. In Groups 1, 3, and 4, no or very slight expression of these markers was observed. The results of this study showed that sperm production in the testes is negatively affected in CUMS-induced depression and that Cas-8, IL-6, and RANKL expression is increased, particularly in interstitial cells. VTX and FLU, used in the treatment of depression, suggest potential for mitigating the adverse effects of CUMS on the testes.