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Rebamipide modulates the miR-29a/SIRT1/FoxO3a and NF-κB pathways in methotrexate-induced testicular damage
Nagla A El-Shitany1, Nageh Ahmed El-Mahdy1, Ola Mahmoud Waly1
1Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Abstract:
Methotrexate (METH) is an effective chemotherapeutic drug that treats diverse cancer types. Unfortunately, it produces toxic effects on the reproductive organs. The current work investigated the role of rebamipide (REBA) in alleviating testicular toxicity caused by METH. Furthermore, the REBA effect on the anticancer activity of METH was examined. Twenty male rats were allocated into four groups: control (CONT), REBA, METH, and REBA + METH groups. METH caused testicular toxicity; it significantly decreased serum testosterone and Johnsen's score and significantly increased Cosentino's score. REBA pretreatment significantly decreased Cosentino's score, malondialdehyde (MDA), interleukin-6 (IL-6), the testicular expressions of nuclear factor kappa B p65 (NF-κB p65), tumor necrosis factor alpha (TNF-α), p53, and microRNA-29a (miR-29a) in comparison to the METH group. REBA caused a significant increase in Johnsen's score, serum testosterone, total antioxidant capacity (TAC), testicular superoxide dismutase (SOD), catalase (CAT), silent information regulator (SIRT1), forkhead box O3a (FoxO3a), and nuclear factor erythroid 2-related factor 2 (Nrf2). Besides, REBA pretreatment potentiated the anticancer activity of METH in a mouse model of Ehrlich solid carcinoma (ESC) (histology with scoring). It was concluded that REBA protected against METH-induced testicular toxicity through modulating the miR-29a/SIRT1/FoxO3a, inflammation, and apoptosis pathways.
Insights
Rebamipide (REBA) protects against methotrexate (METH)-induced testicular toxicity by reducing inflammation and apoptosis. REBA also enhances METH
Area of Science:
- Reproductive Toxicology
- Cancer Chemotherapy
- Drug Development
Background:
- Methotrexate (METH) is a vital chemotherapeutic agent but causes significant testicular toxicity.
- Understanding mechanisms to mitigate METH-induced reproductive side effects is crucial for patient care.
Purpose of the Study:
- To investigate the protective role of rebamipide (REBA) against METH-induced testicular damage.
- To evaluate REBA's impact on METH's anticancer efficacy.
Main Methods:
- Male rats were assigned to control, REBA, METH, or REBA + METH groups.
- Biochemical markers (testosterone, MDA, IL-6, TAC, SOD, CAT), histological scores (Johnsen's, Cosentino's), and molecular expressions (NF-κB p65, TNF-α, p53, miR-29a, SIRT1, FoxO3a, Nrf2) were assessed.
- Anticancer activity was evaluated in a mouse model of Ehrlich solid carcinoma (ESC).
Main Results:
- METH significantly induced testicular toxicity, evidenced by decreased testosterone and Johnsen's score, and increased Cosentino's score.
- REBA pretreatment ameliorated METH-induced toxicity, reducing oxidative stress and inflammation markers (MDA, IL-6, NF-κB p65, TNF-α).
- REBA enhanced METH's anticancer activity and improved testicular function markers (testosterone, Johnsen's score, TAC, SOD, CAT, SIRT1, FoxO3a, Nrf2).
Conclusions:
- Rebamipide effectively protects against methotrexate-induced testicular toxicity.
- REBA modulates key pathways including miR-29a/SIRT1/FoxO3a, inflammation, and apoptosis.
- REBA shows potential as a co-therapeutic agent to improve METH treatment outcomes.
