Candesartan in a rat model of testicular toxicity: New insight on its protective mechanism

Abstract

Cisplatin (CDDP) is widely used as an effective chemotherapy; nevertheless, its use is associated with male reproductive system damage. Candesartan (Cand) is an angiotensin II receptor blocker which showed a protective effect against CDDP-induced testicular toxicity. This study was implemented to investigate further novel molecular protective effect of Cand. Animals were divided into four groups and treated for 10 days as: Group I (Normal control): received saline, Group II (Cand control): treated with Cand (10 mg/kg/day) orally, Group III (CDDP): injected with a single dose of 10 mg/kg CDDP intraperitoneally (ip), Group IV (Cand + CDDP): treated with Cand (10 mg/kg/day) orally plus a single ip dose of 10 mg/kg CDDP at day 3. Blood and testicular tissue collections were done at the end of the experiment. A marked decrease in testicular, body, and relative body weights in addition to testosterone level was observed in the CDDP group when compared with normal rats. In addition, exposure to CDDP showed a marked upregulation of testicular TNF-α mRNA level and a significant rise in testicular levels of total oxidant status, oxidative stress index (OSI) ratio, pro-apoptotic protein Bax, Bax/Bcl-2 ratio alongside with a marked reduction in testicular levels of total antioxidant status, antiapoptotic protein Bcl-2, and a significant upregulation of the testicular caspase-3 expression in comparison to normal group. Histopathological findings after CDDP injection showed apoptosis and necrosis in testicular tissues. Administration of Cand ameliorated these biochemical and histopathological findings. Cand exhibited a novel protective mechanism against CDDP induced-gonadal damage via antioxidant, anti-inflammatory, and anti-apoptotic activities.

Impact statement

Cisplatin is a commonly used drug in the treatment of solid tumors and its application is associated with testicular toxicity. The effect of candesartan in cisplatin-induced testicular toxicity and its fundamental mechanism of action were investigated. Candesartan had certainly repaired the testicular injury and ameliorated both biochemical and histopathological changes. Candesartan mitigated the gonadotoxicity induced by cisplatin via antioxidative, anti-inflammatory, and antiapoptotic actions.