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Evaluation of cell death and immunoexpression of testosterone, EGF and V-ATPase in submandibular glands of rats treated with the antiandrogenic cimetidine

Grant number: 18/25409-2
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2019
Effective date (End): December 31, 2019
Field of knowledge:Biological Sciences - Morphology - Histology
Principal Investigator:Estela Sasso Cerri
Grantee:Mariane Castro Manzato
Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


The saliva is essential for mastication, deglutition and digestion; therefore, hyposalivation impairs the oral health. Saliva pH is maintained by the action of V-ATPase enzyme (proton pump), which control ion exchanges during the passage of saliva through the glandular ducts. The process of salivary secretion is controlled by several factors, including histamine and steroid hormones such as androgens. When testosterone binds to androgen receptors in the glandular tissues, the cells produce EGF (Epidermal Growth Factor), which mediates cellular proliferation, differentiation, cellular migration and apoptosis. Cimetidine, a histamine H2 receptor antagonist, is clinically used for the treatment of gastric and duodenal ulcers, as well as some types of cancer. However, in male patients, this drug has caused sexual dysfunctions due to its antiandrogenic effect. The adverse effects of cimetidine in the male reproductive system of rodents have been reported in the literature; however, scarce studies have focused on the effect of this drug on the salivary glands histophysiology. A recent study demonstrated that cimetidine causes reduction in the AR immunoexpression and structural changes in the submandibular glands of rats. However, the relationship between these changes and the structural and functional integrity of these glands needs to be better investigated. In this study, the structural integrity of submandibular glands and the immunoexpression of testosterone and EGF in these glands will be evaluated in male rats treated with cimetidine for long period. The effect of this drug on the immunoexpression of V-ATPase will also be investigated. Ten male adult rats will be distributed into two groups: control (CG=5) and cimetidine (CMTG=5). The animals will received intraperitoneal injections of 100mg/kg of cimetidine for 52 days. The control animals will receive saline. The submandibular glands will be processed for historesin and paraffin embedding. The structural integrity of the glands will be evaluated in the H.E.-stained historesin sections. The parafin sections will be submitted to TUNEL method (apoptosis detection) and to the immunofluorescence reactions for detection of testosterone, EGF and V-ATPase. The number of TUNEL-positive cells and the immunofluoescence reaction will be quantified. The comparison between the groups will be statistically analyzed by the Student t-test (pd0,05).

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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)
MANZATO, MARIANE CASTRO; DE SANTI, FABIANE; SOUZA A SILVA, ANDRE ACACIO; BELTRAME, FLAVIA L.; CERRI, PAULO S.; SASSO-CERRI, ESTELA. Cimetidine-induced androgenic failure causes cell death and changes in actin, EGF and V-ATPase immunoexpression in rat submandibular glands. Journal of Anatomy, v. 239, n. 1, . (18/25353-7, 17/19829-6, 18/25409-2)

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