Vortioxetine protects against methotrexate-induced ovarian toxicity through anti-inflammatory, antioxidant and antiapoptotic pathways: a multi-marker immunohistochemical study

Abstract

Aims

Methotrexate (MTX), a commonly used chemotherapeutic and immunosuppressive agent, is known to induce significant ovarian toxicity through mechanisms involving oxidative stress, inflammation, and apoptosis. Vortioxetine (VTX), a novel antidepressant with proven neuroprotective and anti-inflammatory properties, has not yet been evaluated in the context of chemotherapy-induced gonadotoxicity. This study aimed to investigate the protective effects of VTX against MTX-induced ovarian injury in a rat model by employing comprehensive histopathological and immunohistochemical evaluations.

Methods and Results

Thirty-two adult female Wistar Albino rats (300–350 g) were randomly divided into four equal groups (n = 8): Control, MTX, MTX + VTX, and VTX. Ovarian damage was induced with a single intraperitoneal injection of MTX (20 mg/kg), while VTX was administered daily (10 mg/kg) by oral gavage for five days. Rats were sacrificed on day 5, and bilateral ovaries were collected. Histopathological evaluation included follicular degeneration, vascular congestion, hemorrhage, and inflammatory cell infiltration. Immunohistochemical analyses were performed for 8-Hydroxy-2'-deoxyguanosine (8-OHdG), nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), caspase 3 (Cas-3), and Anti-Müllerian hormone (AMH) to assess oxidative stress, inflammation, apoptosis, and ovarian reserve. MTX administration caused severe follicular atresia, hemorrhage, and dense neutrophil infiltration. Immunohistochemically, 8-OHdG, NF-κB, TNF-α, and Cas-3 expressions were significantly elevated, while AMH was markedly reduced. VTX co-treatment significantly attenuated histological damage and modulated the expression of all biomarkers, indicating potent protective effects. VTX alone did not induce deleterious changes.

Conclusion

VTX exhibits a robust protective effect against MTX-induced ovarian injury via suppression of oxidative stress, inflammatory response and apoptotic pathways, while simultaneously preserving ovarian reserve. These findings highlight a novel application for VTX in fertility preservation strategies during chemotherapeutic interventions.