Background Methotrexate (MTX) commonly causes oral mucositis by inducing epithelial cytotoxicity and inflammation, leading to functional impairment and treatment limitations. Therefore, agents that can protect oral tissues without reducing MTX efficacy are needed. Vortioxetine (VOR), with its reported anti-inflammatory and antioxidant actions, may offer such therapeutic potential. Methods Thirty-two adults female Wistar rats were divided into four groups: Control, MTX, VOR and MTX + VOR (n = 8 each), weighed 300–350 g and were 10–12 weeks old. VOR (10 mg/kg/day, intraperitoneally [i.p.]) was administered continuously for five days and a single dose of MTX (20 mg/kg, i.p.) was injected 30 min after the first VOR dose on day 1. On day 5, maxillary gingival and tongue tissues were carefully harvested for comprehensive analyses. Histopathological evaluation was performed to assess structural alterations, while immunohistochemical staining was conducted to determine the expression levels of caspase-3 (Casp3) and tumor necrosis factor-alpha (Tnfa). In addition, molecular analyses were carried out to quantify the gene expression profiles of sirtuin 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a), B-cell lymphoma 2 (Bcl2), and Bcl2-associated X protein (Bax), thereby enabling a comprehensive evaluation of apoptotic, inflammatory, and oxidative stress–related pathways. Results MTX treatment caused increased Tnfa and Casp3 immunoexpressing, leading to severe epithelial degeneration, hyperemia and inflammatory cell infiltration in the oral mucosa. Gene expression analysis supported that there was a significant upregulation of proapoptotic (Bax, Casp3) and inflammatory markers (Tnfa) whereas a downregulation of mitochondrial regulators (Sirt1, Nrf2, Ppargc1a, Bcl2). Co-treatment with VOR markedly reversed these changes. Conclusion VOR significantly ameliorated the damage caused by MTX to the oral mucosa by interfering with the Sirt1/ Nrf2/ Ppargc1a antioxidant axis and suppressing the Bax/Bcl2/ Casp3 apoptotic pathway. These results indicate that VOR can be used as a valuable therapeutic agent that can be combined with chemotherapy to alleviate side effects in the oral mucosa by restoring redox homeostasis, mitochondrial integrity and cellular survival signals.

Vortioxetine mitigates methotrexate-induced oral mucosa injury via sirtuin 1 pathway and intrinsic apoptosis signaling

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2026年3月27日

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Mustafa Karaca,
Burcu Bakir,
Aybike Imeci,
Esma Selcuk,
Halil Asci,
Ozlem Ozmen

摘要

Background

Methotrexate (MTX) commonly causes oral mucositis by inducing epithelial cytotoxicity and inflammation, leading to functional impairment and treatment limitations. Therefore, agents that can protect oral tissues without reducing MTX efficacy are needed. Vortioxetine (VOR), with its reported anti-inflammatory and antioxidant actions, may offer such therapeutic potential.

Methods

Thirty-two adults female Wistar rats were divided into four groups: Control, MTX, VOR and MTX + VOR (n = 8 each), weighed 300–350 g and were 10–12 weeks old. VOR (10 mg/kg/day, intraperitoneally [i.p.]) was administered continuously for five days and a single dose of MTX (20 mg/kg, i.p.) was injected 30 min after the first VOR dose on day 1. On day 5, maxillary gingival and tongue tissues were carefully harvested for comprehensive analyses. Histopathological evaluation was performed to assess structural alterations, while immunohistochemical staining was conducted to determine the expression levels of caspase-3 (Casp3) and tumor necrosis factor-alpha (Tnfa). In addition, molecular analyses were carried out to quantify the gene expression profiles of sirtuin 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a), B-cell lymphoma 2 (Bcl2), and Bcl2-associated X protein (Bax), thereby enabling a comprehensive evaluation of apoptotic, inflammatory, and oxidative stress–related pathways.

Results

MTX treatment caused increased Tnfa and Casp3 immunoexpressing, leading to severe epithelial degeneration, hyperemia and inflammatory cell infiltration in the oral mucosa. Gene expression analysis supported that there was a significant upregulation of proapoptotic (Bax, Casp3) and inflammatory markers (Tnfa) whereas a downregulation of mitochondrial regulators (Sirt1, Nrf2, Ppargc1a, Bcl2). Co-treatment with VOR markedly reversed these changes.

Conclusion

VOR significantly ameliorated the damage caused by MTX to the oral mucosa by interfering with the Sirt1/ Nrf2/ Ppargc1a antioxidant axis and suppressing the Bax/Bcl2/ Casp3 apoptotic pathway. These results indicate that VOR can be used as a valuable therapeutic agent that can be combined with chemotherapy to alleviate side effects in the oral mucosa by restoring redox homeostasis, mitochondrial integrity and cellular survival signals.