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Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, immunosuppressive, cytotoxic drugs with reported adverse effects, including oxidative damage to testis. This study aims to evaluate the potential effect of grape seed extract (GSE; gervital) to prevent testicular damage caused by MTX and AZA. Male albino rats were separated into six groups: group I, normal control group; group II, GSE (150 mg/kg/day); group III, MTX (8 mg/kg/week); group IV, AZA (15 mg/kg/day); group V, GSE (150 mg/kg/day) + MTX (8 mg/kg/week); group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). All rats were sacrificed, blood samples were obtained for testosterone analysis, and testis was removed for histological and ultrastructural studies and oxidation measurements. A reduction in relative body and testis weight, along with a significant decrease in testosterone levels, was observed. Histopathological and ultrastructural alterations induced by MTX or AZA included reduced spermatozoa, sloughing, marked reduction of spermatogenic cells, and pyknosis of some nuclei. Significant oxidative stress manifested as reduced glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities, as well as increased malondialdehyde (MDA) levels. GSE administration showed an ameliorative effect on testosterone levels and histopathological and ultrastructural changes. GSE treatment also suppressed the increases in MDA levels and the decreases in GSH levels and CAT and SOD activities. In conclusion, these findings confirm that GSE is an effective antioxidant that protects testis from histopathological and ultrastructural damage induced by MTX and AZA. Therefore, GSE is a promising candidate for future use to minimize and alleviate MTX and AZA risks. Graphical abstract

Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, immunosuppressive, cytotoxic drugs with reported adverse impacts such as oxidative damage to testis. This study aims to scrutinize the potential effect of grape seed extract (GSE; gervital) to prevent testicular damage propelled by MTX and AZA. Rats were separated into six groups: Group I, normal control group; Group II, GSE (150 mg/kg/day); Group III, MTX (8 mg/kg/week). Group IV, AZA (15 mg/kg/day). Group V, GSE (150 mg/kg/day) + MTX (8 mg/kg /week); Group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). All rats were sacrificed, blood samples were obtained for testosterone analysis and testis was removed for histological, ultrastructural studies and oxidation measurements. A reduction in body and testes relative weight, along with a significant decrease in testosterone was observed. Histopathological, ultrastructural alterations induced by MTX or AZA include scanty spermatozoa, sloughing, marked reduction of spermatogonia cells, and pyknosis of some nuclei. Significant oxidative stress (OS) manifested by reduced glutathione (GSH) level, catalase (CAT) and superoxide dismutase (SOD) as well as increase in malondialdehyde (MDA) levels. GSE administration showed an ameliorative effect on testosterone, histopathological and ultrastructural changes. GSE treatment also suppressed the increases in MDA levels and the decrease in GSH level, CAT, and SOD activities. Conclusion, our findings confirmed that GSE is an effective antioxidant that prevent and protect testis from the histopathological and ultrastructural damages induced by MTX and AZA. So, GSE is a promising candidate for future use to minimize and alleviate MTX and AZA risks