Pharmacological evaluation of compound 4C to prevent priapism in transgenic sickle cell mice

• Grant number: 14/21965-7
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): March 01, 2015
• Effective date (End): February 29, 2016
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Fábio Henrique da Silva
• Supervisor abroad: Arthur Louis Burnett
• Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Local de pesquisa : Johns Hopkins University (JHU), United States
• Associated to the scholarship: 13/19781-2 - Therapeutic prevention of priapism in transgenic sickle cell mice with drugs that interfere on the NO/sGC/cGMP signaling pathway, BP.PD

Abstract

Priapism is defined as a penile erection that persists beyond or is unrelated to sexual interest or stimulation, and is one of the complications associated with sickle cell disease (SCD). This condition constitutes a urological emergency requiring prompt diagnosis and treatment, since it is associated with erectile tissue damage and erectile dysfunction, a known complication. Current therapies offered for this condition are nonpreventive and often administered too late during an episode of priapism. Therefore, novel therapies for preventing and treating priapism in SCD are still necessary. Recent studies suggest that priapism in SCD is associated with decreased nitric oxide (NO) bioavailability, leading to compensatory downregulation of phosphodiesterase type 5 (PDE5) protein expression and activity, thus impairing a control mechanism of penile erection. In addition, increased oxidative stress contributes to endothelial dysfunction and cavernosal tissue damage in SCD. Thus, therapies that normalize NO bioavailability, restore NO-cGMP-PDE5 signaling pathway and reduce oxidative stress in the penis may be of important clinical interest. In a continuing effort to develop new candidate drugs to treat SCD symptoms, compound 4c was synthesized by molecular hybridization of hydroxyurea and thalidomide. This compound demonstrates NO-donor, analgesic, anti-inflammatory and TNF-± inhibitory properties, as well as the capacity to stimulate the production of fetal hemoglobin. Therefore, compound 4c is novel drug candidate with multiple beneficial actions for the treatment of SCD symptoms. This project aims to evaluate the pharmacological effect of continuous treatment with compound 4c, with a view to reversing the erectile function alterations that are associated with a dysregulated NO-GMPc-PDE5 signaling pathway and increased oxidative stress in transgenic sickle cell mice. (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)

SILVA, FABIO H.; KARAKUS, SERKAN; MUSICKI, BILJANA; MATSUI, HOTAKA; BIVALACQUA, TRINITY J.; DOS SANTOS, JEAN L.; COSTA, FERNANDO F.; BURNETT, ARTHUR L. Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment. Journal of Pharmacology and Experimental Therapeutics, v. 359, n. 2, p. 230-237, NOV 1 2016. Web of Science Citations: 4.