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Influence of exogen melatonin on rat prostate tissue response to experimental diabetes and interference on androgen and insulin actions

Abstract

Experimental evidence indicates that diabetes leads to atrophy,proliferation and cell death imbalance and increase incidence of malignantand pre-malignant lesions in the prostate. The low androgen levels and changes in insulin signaling have been implicated in these responses, but the role of oxidative stress should be further clarified. The neurohormonemelatonin has been widely used in treatment of diseases such as diabetes and cancer due to its antioxidant action. The anti-mitotic action of melatonin on prostate cancer cell lines is well established. However, informations about the effects of in vivo treatment with this hormone and the possible interference in prostate alterations due to diabetes are scarse. This studyaimed to examine whether exogenous melatonin attenuates the tissue damage caused on prostate by experimental diabetes and its influence in theantioxidant system of the gland. First, we will investigate if treatment of Wistar rats with low doses of melatonin, since pre-puberty to adulthood, alters prostatic histophysiology and anti-oxidant system under diabetes in theshort- and medium-term (experiment 1). This experiment will also examine whether melatonin treatment affects the prostate maturation and histology of normal animals in adulthood, the levels of proliferation and cell death andandrogen sensitivity. In a second step will be evaluated whether treatment with high doses of melatonin from the experimental diabetesinduction in rats interferes with the gland response to the disease(experiment 2). Male Wistar rats (n = 10 per group/ total 120) will be divided into control (C), control treated with melatonin (M), diabetic (D), diabetic treated with melatonin (DM) groups. In experiment 1,the rats will be treated with melatonin 10ug/ml/day in drinking water) from 5weeks old until the end of the experiment. Diabetes will be induced with 12 weeks old by streptozotocin injection (40mg/kg body weight, ip) and the animals will be euthanized one (C1, M1, D1, DM1) or eight weeks (C2, M2,D2, DM2) after the diabetes onset, for analysis of short- and medium-term, respectively. In experiment 2, diabetes will be induced in adult male rats (12 weeks old) at the same day of melatonin treatment initiation (5mg/kg/day by gavage) and the groups (C3, M3, D3, DM3) will be euthanized one week after diagnosis of diabetes. The ventral prostate will be processed for microscopic and biochemical analysis, and serum blood samples will be prepared for hormonal measurements. The following parameters will be assessed using light microscopy: : histological appearance, volume fractions of the major tissue compartments, incidence and multiplicity ofpre-malignant and malignant tissue lesions and cell death levels (TUNEL method). It will also be examined by immunocitochemistry the cell proliferation levels, androgen receptor (AR) positive cell numbers and the distributionof melatonin receptors (MT1 and MT2). The protein expression of AR, PCNA, MT1 and MT2 in the gland will be analyzed by Western blotting. The serumlevels of estrogens, testosterone and melatonin will be determined by ELISA, respectively. The activity of antioxidant enzymes superoxidedismutase, catalase, glutathione peroxidase and glutathione transferase and of lipid peroxidation levels, will be assessed in blood samples and in the prostate, using specific biochemical assays, in both experiments. This research will bring experimental information about the effects of treatment with this anti-oxidant hormone for prostatic histophysiology and its possible protective role against diabetes. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
TAMARINDO, GUILHERME H.; RIBEIRO, DANIELE L.; GOBBO, MARINA G.; GUERRA, LUIZ H. A.; RAHAL, PAULA; TABOGA, SEBASTIAO R.; GADELHA, FERNANDA R.; GOES, REJANE M. Melatonin and Docosahexaenoic Acid Decrease Proliferation of PNT1A Prostate Benign Cells via Modulation of Mitochondrial Bioenergetics and ROS Production. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2019. Web of Science Citations: 2.
NEGRIN, ANA CAROLINA; DE JESUS, MARIANA MARCIELO; CHRISTANTE, CAROLINE MARIA; HUMBERTO DA SILVA, DANILO GRUNIG; TABOGA, SEBASTIAO ROBERTO; PINTO-FOCHI, MARIA ETELVINA; GOES, REJANE MAIRA. Maternal supplementation with corn oil associated or not with di-n-butyl phthalate increases circulating estradiol levels of gerbil offspring and impairs sperm reserve. REPRODUCTIVE TOXICOLOGY, v. 81, p. 168-179, OCT 2018. Web of Science Citations: 3.

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