Role of EGF/ERK1/2/HO-1 axis in mediating methotrexate induced testicular damage in rats and the ameliorative effect of xanthine oxidase inhibitors

Abstract

Objectives: Methotrexate (MTX) is commonly used in the management of several malignancies and autoimmune disorders; however, testicular damage is one of the most detrimental effects of MTX administration. The current the protective effect of xanthine oxidase inhibitors either purine analogue; allopurinol (ALL) or non-purine analogue; febuxostat (FEB) in testicular injury induced by MTX in rats.

Materials and methods: Thirty-two rats were randomly allocated to four groups; control (received vehicles), MTX (received single dose, 20 mg/kg, i.p.), MTX + ALL (received MTX plus ALL) and MTX + FEB (received MTX plus ALL). ALL and FEB were administered orally at 100- and 10 mg/kg, respectively for 15 days. Total and free testosterone were measured in serum. In addition, total antioxidant capacity (TAC), epidermal growth factor (EGF), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), extracellular signal-regulating kinase1/2 (ERK1/2), and total nitrite/nitrate (NOx) end products were measured in testicular tissues. At the same time, immunoexpression of HO-1in testicular tissue was measured. Histopathological examination was done.

Results: ALL and FEB increased total and free serum testosterone. Both drugs showed a significant reduction in testicular MDA, NOx, TNF-α levels with an increase in TAC, EGF, and ERK1/2 levels in testicular tissue. Furthermore, both drugs enhanced HO-1 immunoexpression in testicular tissue. All these findings were parallel to the preservation of normal testicular architecture in rats treated with ALL and FEB.

Conclusion: All and FEB were equally protective against testicular damage induced by MTX through anti-inflammatory, anti-apoptotic, and antioxidant actions. Their effects might be through activation of the EGF/ERK1/2/HO-1 pathway.

Keywords:

• Xanthine oxidase inhibitors
• methotrexate
• epidermal growth factor
• heme oxygenase-1
• ERK_1/2
• testicular damage

Ethical approval

Study was approved by the Institutional Ethical Committee (Faculty of Medicine, Minia University, Egypt) (Approval number 325:11/2019).

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Author contributions

RR and RM designed and performed the experiment, data analysis, and supervision. MI and WA cooperated in performing the experiment, revised manuscript, and wrote the final draft. NE performed the histopathological studies. The authors declare that all data were generated in-house and that no paper mill was used.

Disclosure statement

The authors declare that they have no conflicts of interest.

Additional information

Funding

This study did not extradite any specific confer from funding agencies in the public, commercial, or not-for-profit sectors.