Abstract
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. In the current study, we evaluated the possible 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. Gonadotoxicity was induced by a single dose of MTX (20 mg/kg, i.p.). ALL and FEB were administered orally in the following daily doses (100, 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 nitric oxide (NO) end products were measured in testicular tissues. At the same time, immunoexpression of HO-1in testicular tissue was measured. Histopathological examination was done. ALL and FEB increased total and free serum testosterone. Both drugs showed a significant reduction in testicular MDA, NO, 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. In conclusion, All and FEB were protective against testicular damage induced by MTX through anti-inflammatory, anti-apoptotic, and antioxidant actions which might be through activation of the EGF/ERK1/2/HO-1 pathway. At the same time, no significant difference between ALL and FEB was noticed in this protective effect.