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Immunohistochemical evaluation of the action of zoledronate during healing process of soft tissue overlying the site of tooth extraction in rats with main risk factors for osteonecrosis of the jaws

Grant number: 14/14118-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2014
Effective date (End): November 30, 2015
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Edilson Ervolino
Grantee:João Martins de Mello Neto
Home Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil

Abstract

Bisphosphonates (BPs) are a class of drugs used in the treatment of some bone diseases or osteotropic malignancies. BPs exert potent inhibitory effect on bone resorption. Among the adverse effects is the occurrence of bisphosphonate-related osteonecrosis of the jaws (BRONJ). The risk factors for the onset of BRONJ are: chronic use of nitrogen-containing- BPs, especially zoledronate, intravenous route of administration, female gender, older age and oral surgeries, especially exodontia. The pathogenesis of the disease is poorly understood, which hinders its prevention and treatment. Some in vitro studies point to an action of BPs in the soft tissues, especially those overlying the site of tooth extraction. The action of BPs on these cells needs further investigation because it could help to elucidate the pathogenesis of ONJ. The purpose of this study is to evaluate in vivo the effect of chronic therapy with zoledronate during healing process of soft tissue overlying the site of tooth extraction in rats that show the main risk factors for the development of BRONJ. Forty-two rats (females; 20-month-old) will be divided into two experimental groups, SAL and ZOL, which will be submitted to a treatment plan for seven weeks. SAL group will receive 0.45 ml of 0.9% sodium chloride by intraperitoneal injection. ZOL group will receive 0.45 ml of 0.9% sodium chloride added 100 mg/kg zoledronate by intraperitoneal injection. The interval between applications of zoledronate or vehicle will be two days. After three weeks of treatment, all rats will be submitted to the exodontia of right mandibular first molar. Then each of these groups will be divided into three subgroups, each consisting of 7 animals : SAL-7d and ZOL-7d, SAL-14d and ZOL-14d, SAL-28d and ZOL-28d, whose animals will be euthanized 7, 14 and 28 postoperative days, respectively. Subsequently, the hemi-mandibles will undergo histological processing. Histological sections of the mucosa overlying the site of tooth extraction will be subjected to immunohistochemical detection of: proliferating cell nuclear antigen (PCNA), BCL-2 associated X protein (BAX), cleaved caspase-3, hypoxia inducible factor-1 alfa (HIF-1a), vascular endothelial growth factor (VEGF) and platelet/endothelial cell adhesion molecule-1 (PECAM-1). Results will be analyzed under light microscopy and will be submitted to quantication and statistical analysis at 5% significance level.

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)
STATKIEVICZ, CRISTIAN; TORO, LUAN FELIPE; DE MELLO-NETO, JOAO MARTINS; DE SA, DANIELA PEREIRA; CASATTI, CLAUDIO APARECIDO; MARDEGAN ISSA, JOAO PAULO; ANGELO CINTRA, LUCIANO TAVARES; DE ALMEIDA, JULIANO MILANEZI; HITOMI NAGATA, MARIA JOSE; GARCIA, VALDIR GOUVEIA; THEODORO, LETICIA HELENA; ERVOLINO, EDILSON. Photomodulation multiple sessions as a promising preventive therapy for medication-related osteonecrosis of the jaws after tooth extraction in rats. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 184, p. 7-17, JUL 2018. Web of Science Citations: 6.

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