Abstract
This study aimed to investigate the protective role of resveratrol (RES) against cisplatin (Cis)-induced testicular damage and reproductive dysfunction in rats and to examine the underlying mechanisms of protection including its effect on endoplasmic reticulum (ER) stress, P53, extracellular signal-regulated kinase (ERK)-1/2, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and Protein kinase B (Akt) signaling. Eight-week-old Rats were divided into four groups (n = 12 each) of 1) control group: received normal saline (i.p.) as vehicle for 45 days, 2) RES-treated group: received RES (20 mg/kg, i.p) for 45 days, 3) Cis-treated group: received Cis (3 mg/kg) for 3 days and then continued on normal saline, and 4) Cis + RES-treated group: received Cis for the first 3 days and then continued on RES for the next 45 days. Serum sex hormones levels, sperm parameters, and levels of testicular antioxidant potential and inflammatory mediators were assessed in all rats. In addition, activation of ER stress, P53, ERK1/2, JNK, and Akt and markers of apoptosis were evaluated in rats' testis. Cis lowered sperm count and motility and increased sperm morphological abnormalities. Testis of Cis-treated rats had low expression of antioxidant enzymes including SOD, CAT, and GPx and decreased the level of GSH. Concomitantly, Cis upregulated levels of cleaved caspase-3, P53, calpain-1/cleaved caspase-12, p-ERK1/2, and p-SAPK/p-JNK. However, RES administration post-Cis administration restored all sperm parameters and prevented testicular apoptosis mediated by inhibition of all above-mentioned apoptotic pathways. Moreover, RES enhanced testosterone, FSH, and LH levels and upregulated p-Akt/p-Bad levels in both control and Cis-treated rats. In conclusion, RES protects against Cis-induced testicular damage and reproductive dysfunction via improving testosterone levels, increasing sperm count, reducing testicular apoptosis via an antioxidant potential, inhibition of ER stress, P53, ERK1/2, JNK, and activation of Akt. Abbreviations: RES: resveratrol, Cis: cisplatin; ER: endoplasmic reticulum; ERK1/2: extracellular signal-regulated kinase1/2; SAPK/JNK: stress-activated protein kinase/c-Jun N-terminal kinase; Akt: protein kinase B; HPG axis: hypothalamic-pituitary-gonadal axis; PUFAs: polyunsaturated fatty acids; FSH: Follicular stimulating hormone; LH: Luteinizing hormone; PBS: phosphate buffered saline; GSH: reduced glutathione; GSSG: glutathione disulfide; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; GRx: glutathione reductase; SOD: superoxide dismutase; CAT: catalase; 4HNE: 4-hydroxynonenal.