Therapeutic prevention of priapism in transgenic sickle cell mice with drugs that interfere on the NO/sGC/cGMP signaling pathway.

• Grant number: 13/19781-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2014
• End date: February 28, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Fábio Henrique da Silva
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 14/21965-7 - Pharmacological evaluation of compound 4C to prevent priapism in transgenic sickle cell mice, BE.EP.PD

Abstract

Epidemiological studies have shown that 30-45% of men with sickle cell disease reported episodes of ischemic priapism and of these 30% develop erectile dysfunction. Episodes of recurrent priapism require constant support of emergency medical center, impairing the patients' quality of life, particularly the well-being, and family and social interrelationships. Despite the frequency of priapism, the treatments available act acutely and not in the prevention. Currently, it is understood that it is essential the development of new therapies for the prevention of priapism. Paradoxically, recent evidences show that the reduction of nitric oxide (NO) bioavailability in the corpus cavernosum is the major cause for the development of priapism in sickle cell disease. The authors showed that the reduction of endothelial NO bioavailability results in a compensatory downregulation of phosphodiesterase type 5 (PDE5) protein expression and activity, thus impairing the control mechanism of penile erection. These authors suggest that the normalization of basal NO/cGMP levels may restore the PDE5 protein expression and activity, and consequently the control regulatory of penile erection. Thus, compounds that act in the normalization of basal NO/cGMP levels in corpus cavernosum may be a good therapeutic strategy for prevention of priapismo in sickle cell disease. Therefore, the present work aims to evaluate the pharmacological effect of chronic treatment with modulators agents of NO-sGC-cGMP signaling pathway, compound 4c, BAY 73-6691 and hydroxyurea, and to compare with sildenafil (positive control), aiming to restore the alterations of erectile function associated with reduction of NO bioavailability in transgenic sickle cell mice.

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.; CLAUDINO, MARIO A.; CALMASINI, FABIANO B.; ALEXANDRE, EDUARDO C.; FRANCO-PENTEADO, CARLA; BURNETT, ARTHUR L.; ANTUNES, EDSON; COSTA, FERNANDO F.. Sympathetic Hyperactivity, Increased Tyrosine Hydroxylase and Exaggerated Corpus Cavernosum Relaxations Associated with Oxidative Stress Plays a Major Role in the Penis Dysfunction in Townes Sickle Cell Mouse. PLoS One, v. 11, n. 12, DEC 9 2016. (14/00984-3, 13/19781-2)

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. (14/00984-3, 10/12495-6, 13/19781-2, 14/21965-7)