Effect of pharmacological treatment with mimetic peptide of Annexin A1 in the cisplatin-induced ototoxicity in wistar rats

• Grant number: 18/08764-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2018
• End date: December 31, 2019
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Cristiane Damas Gil
• Grantee: Letícia da Silva Sena
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Cisplatin is an antineoplastic agent largely used and related to bilateral and irreversible hearing loss in patients. Generation of reactive oxygen species (ROS) by cisplatin induces cochlear inflammation and apoptosis of cochlear cells. Thus, therapeutic strategies seeking to reduce auditory dysfunction through the prevention of inflammation have been studied. In this context, we highlight annexin A1 (ANXA1), a 37kDa protein able to mimic the anti-inflammatory action of glucocorticoids by inhibiting the synthesis of eicosanoids and phospholipase A2, affecting components of the inflammatory reaction and release of arachidonic acid. In addition, the regulatory action of ANXA1 and its mimetic peptides on transendothelial leukocyte migration is mediated by the formyl peptides receptor 2 (Fpr2), a transmembrane receptor attached to G protein. In the present study, we will evaluate the effect of the pharmacological treatment with the ANXA1 mimetic peptide, Ac2-26, on the cisplatin-induced ototoxicity in Wistar rats. Animals will be divided into three groups (n= 6 animals): Group A - will receive three doses of cisplatin (8mg/kg) i.p. per day, totaling a treatment of 24mg/kg in 3 days; Group B - will receive pharmacological treatment with 1 mg/kg of Ac2-26, i.p., 15 minutes before cisplatin administration (3 days); Group C- SHAM (control), will receive vehicle (sterile saline). Rats will be submitted to distortion product otoacoustic emissions (DPOAEs) before and after treatment, and possible changes in amplitude and noise ratio in the 2, 4, 6 and 8 kHz frequencies will be analyzed. Six hours after the last cisplatin or vehicle dose, animals will undergo euthanasia for the following analyses: I) inner ear histological analysis; II) AnxA1, Fpr2, caspase-3 and extracellular signal-regulated kinase (ERK) levels in inner ear by immunohistochemistry. The results will contribute to knowledge of the cellular and molecular mechanisms that involve the biological actions of AnxA1 in the hearing loss, as well as possible therapeutic targets for the inflammatory processes of the inner ear.