Phoenix Dactylifera Mitigates Fluoxetine-induced Testicular Toxicity in Rats: Dose-dependent Antioxidant and Anti-fibrotic Effects

Abstract

Background: Fluoxetine, which is a selective serotonin reuptake inhibitor (SSRI), is commonly prescribed for the treatment of major depressive disorder, anxiety disorders and obsessive-compulsive disorder. Fluoxetine (FLX), a widely prescribed SSRI, induces testicular toxicity, raising concerns about male fertility. This study evaluated the protective effects of Phoenix dactylifera L. (PDL) methanolic fruit extract against FLX-induced reproductive dysfunction. Aim: The aim of the study is to Dose-Dependent Antioxidant Effects of Phoenix Dactylifera on Fluoxetine-Induced Testicular Oxidative Damage in Rats. Methods: Thirty-six male Wistar rats (200-250 g) were divided into: Control, PDL (200/400 mg/kg), FLX (20 mg/kg), and FLX+PDL groups (n=6/group). Treatments were administered orally for 57 days. We assessed testicular weight, oxidative stress markers (SOD (Superoxide Dismutase), GSH(Glutathione) and MDA(Malondialdehyde)) and histopathology (H&E, Masson's trichrome) after 57 days of treatment. Results: FLX significantly reduced body weight (p<0.05) and testicular weight while increasing MDA (38.19±3.28 vs control 20.10±3.63; p<0.05) and depleting GSH (0.63±0.07 vs 1.14±0.21; p<0.05). Histology revealed seminiferous tubule atrophy, fibrosis and spermatogenic arrest. PDL co-treatment (400 mg/kg) normalized oxidative stress (MDA: 20.28±9.99; GSH: 0.75±0.09) and enhanced SOD activity (12.44±2.59 vs FLX 16.17±3.29). Notably, PDL at 400 mg/kg was more effective than 200 mg/kg in restoring GSH and reducing MDA., showing intact germinal epithelium (higher sperm count) and reduced fibrosis (less collagen). Conclusion: PDL extract effectively ameliorates FLX-induced testicular damage through antioxidant and anti-fibrotic mechanisms, demonstrating potential as an adjunct therapy for SSRI-associated male infertility. These findings support further investigation of PDL for fertility preservation during antidepressant treatment. This study demonstrates that Phoenix dactylifera L. (PDL) methanolic extract effectively mitigates fluoxetine-induced testicular toxicity by attenuating oxidative stress, reducing fibrosis, and preserving spermatogenesis. Future studies should validate these effects in clinical populations and explore the bioactive compounds responsible for PDL’s therapeutic actions.