Cimetidine is clinically used as antiulcer, competing for histamine H2 receptors in gastric parietal cells. Nowadays, this drug has also been used as an adjuvant in some types of cancer therapy because its antiangiogenic effect. This drug also seems to antagonize androgen receptors, exerting an antiandrogenic effect, which has been strongly related to changes in the male reproductive system. Therefore, cimetidine has caused several harmful effects, particularly on the testes and vas deferens. In testes, this drug causes significant changes, both in the seminiferous tubules and in the testicular microvasculature. Additionally, damages in the Leydig cells have also been demonstrated. Recent studies have shown that changes in the seminiferous epithelium, caused by cimetidine, are significantly softened by the supplementation of animals with vitamin B12. Although this beneficial effect has not been clarified, it has been suggested that this vitamin stimulates mitotic and/or meiotic activities in spermatogonia and/or spermatocytes. Thus, regarding the antiandrogenic effect of cimetidine and the scarce literature on the pharmacological action of spermatic ducts in the male reproductive system, it will be proposed to evaluate the effect of cimetidine on the structural integrity of the epididymis, as well as the expression of AR and SHBG. Regarding the changes caused by cimetidine in spermatogenic process and the beneficial effect of vitamin B12 on the seminiferous epithelium, it will also be proposed to evaluate if treatment with cimetidine causes morphological and quantitative changes in sperm cells and changes in spermatic DNA integrity; and to verify whether supplementation with vitamin B12 is able to inhibit or reduce such spermatic changes. In this study, 52 adult rats will be divided into four groups (n=13) and treated with: 100 mg/kg bw of cimetidine (CMTG), 3¼g of vitamin B12 (B12G), cimetidine + B12 (CMT/B12G) and saline (CG). After treatment for 50 days, spermatozoa collected from the left caudal portion of epididymis of 8 animals from each group will be submitted to sperm analysis (morphology, concentration and motility). The right caudal portion of epididymis will be used to evaluate the integrity of spermatic DNA (Comet Assay) and mitochondrial activity. The caudal portions of the epididymis of the remaining animals will be collected, processed and embedded in paraffin and historesin. From CG and CMTG groups, historesin sections will be used for morphological and morphometric analyzes (epididymal diameter, number of clear and principal cells). The paraffin sections will be submitted to immunohistochemical and/or immunofluorescence reactions for detection of AR and SHBG.
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