Diabetes mellitus leads to drastic prostatic atrophy and impairment of secretory capacity. This damage is associated with the imbalance in the epithelial kinetics, remodeling of the extracellular matrix and morph functional changes in stromal cells of the prostate, due mainly to androgen fall, which is typical for this metabolic disorder. However, we can not neglect the hyperglycemia and the consequent oxidative stress in this gland. Melatonin has been widely used as treatment in diseases like diabetes and cancer, since besides controlling hormonal variations according to the photoperiod, this hormone exhibits antioxidant properties. Disturbances in melatonin synthesis are associated with diabetes onset and its hole as anti-tumor in prostate cancer is due to its anti-mitogenic action. This study aims to examine whether melatonin administration to rats from the pre-puberty since adulthood affects the prostate maturation and histology, interferes at its proliferation and cell death levels and androgen sensitivity. The protective function of melatonin in prostate histophysiology under experimental diabetes in short (one week) and medium (eight weeks) will be evaluated. The animals will be weighed and randomly divided into eight groups: control rats (C1), control rats treated with melatonin 1 (M1), short-term diabetic rats (D1), short-term diabetic rats treated with melatonin (DM1), control rats 2 (C2), control rats treated with melatonin 2 (M2), medium-term diabetic rats (D2), medium-term diabetic rats treated with melatonin (DM2). The melatonin will be administered in drinking water (0.4 ug /ml /day) from 5 weeks age until the end of the experiment. For both experiments, the induction of diabetes will be done at 12 weeks age by streptozotocin injection (40mg/kg body weight, ip) and the sacrifice will occur at 13 (experiment 1) and 19 (experiment 2) weeks age. The ventral prostate will be removed and weighed, and the lobes will be processed for light microscopy and frozen for biochemistry. The immunoreaction of androgen receptors (AR), proliferating nuclear antigen (PCNA) of melatonin receptors (MT1 and MT2) will be quantified and the presence of apoptotic cells will evaluated by TUNEL method. Analysis of protein expression of PCNA, MT1 and MT2 receptors in the gland will be performed by Western blotting. Steroids serum levels (estrogen and testosterone) and melatonin will be determined by chemilumescence and HPLC respectively. The antioxidant enzymes activities (superoxide dismutase, catalase, glutathione peroxidase, and glutatione transferase) and lipid peroxidatation levels in blood and prostate extracts will be quantified by specific tests and spectrophotometer. The incidence and multiplicity of premalignant and malignant lesions will be investigated among the different experimental groups. This research certainly will expand the comprehension of melatonin action mechanisms in the prostate. It will also bring experimental data on the effects of prolonged treatment with this anti-oxidant hormone for prostate histophysiology and its possible protective role against diabetes.
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