Priapism and voiding dysfunction in Sickle Cell Disease: pathophysiology and new drug candidates

• Grant number: 17/08122-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: April 01, 2018
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Fábio Henrique da Silva
• Grantee: Fábio Henrique da Silva
• Host Institution: Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil
• Associated researchers: Arthur Louis Burnett ; Fernando Ferreira Costa ; Leonardo Oliveira Reis
• Associated scholarship(s): 23/03966-5 - Characterization of the pathophysiology of voiding dysfunction in transgenic mice for sickle cell disease: molecular analysis, BP.IC; 22/10548-2 - To investigate the contribution of intravascular hemolysis to functional and molecular changes in the bladder in a model of intravascular hemolysis induced by phenylhydrazine (PHZ), BP.MS; 19/17030-6 - Role of intravascular hemolysis on Priapism in transgenic sickle cell mice: therapeutic potential of haptoglobin, BP.MS; 18/12296-5 - Priapism and voiding dysfunction in sickle cell disease: pathophysiology and new drug candidates, BP.IC; 18/06243-6 - Priapism and voiding dysfunction in sickle cell disease: pathophysiology and new drug candidates, BP.JP

Abstract

Priapism is an important clinical problem for patients with Sickle Cell Disease. Despite advances in understanding the pathophysiology of this condition, few studies have aimed at understanding the physiopathological mechanisms involved. To date, there is no satisfactory pharmacological therapy to prevent Priapism. Ideally, new prevention strategies should act on the pathophysiological basis of the disorder. In Sickle Cell Disease, experimental evidences show that reducing the bioavailability of Nitric Oxide (NO) in the penis is one of the main causes that contributes to Priapism. Recently, we have shown that a new NO donor compound, hybrid derived from thalidomide and hydroxyurea, prevents Priapism in transgenic sickle cell mice. In a continuing effort to identify new drug candidates for the treatment of Priapism, this project proposes to evaluate the pharmacological effect of new and promising NO donor compounds in transgenic sickle cell mice. These compounds are hybrids derived from thalidomide, resveratrol and furoxanic nucleus. As research advances in the understanding of Sickle Cell Disease, recent clinical researches have shown that patients with Sickle Cell Disease display Lower Urinary Tract Symptoms (LUTS). About 38% of patients exhibit overactive bladder. However, the pathophysiological mechanisms involved in voiding dysfunction in Sickle Cell Disease are scarce. In general, an important alteration that occurs in Sickle Cell Disease is increased oxidative stress and reduced NO bioavailability. In this context, the present project also proposes to study the alterations of the NO-cGMP signaling pathway and the role of oxidative stress in voiding dysfunction in transgenic sickle cell mice. In Sickle Cell Disease, the reduction of NO bioavailability by hemoglobin is a serious consequence of intravascular hemolysis. Clinical studies show a strong positive correlation between Priapism and increased levels of intravascular hemolysis in men with sickle cell anemia. However, to date, there are no experimental studies corroborating the clinical evidence. In the present project, we hypothesized that reducing the bioavailability of NO by free hemoglobin contributes to Priapism and to voiding dysfunction in Sickle Cell Disease. Therefore, the present project also proposes to study the role of intravascular hemolysis on lower genitourinary tract functions (penis, bladder and urethra) in transgenic sickle cell mice and model of intravascular hemolysis induced by phenylhydrazine in mice. (AU)

Scientific publications

(8)

(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)

MUSICKI, BILJANA; ANELE, UZOMA A.; CAMPBELL, JEFFREY D.; KARAKUS, SERKAN; SHIVA, SRUTI; SILVA, FABIO H.; BURNETT, ARTHUR L.. Dysregulated NO/PDE5 signaling in the sickle cell mouse lower urinary tract: Reversal by oral nitrate therapy. Life Sciences, v. 238, DEC 1 2019. (17/08122-9, 18/06243-6)

PEREIRA, PAMELA DA SILVA; PEREIRA, DALILA ANDRADE; CALMASINI, FABIANO BERALDI; REIS, LEONARDO O.; BRINKMAN, NATHAN; BURNETT, ARTHUR L.; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Haptoglobin treatment contributes to regulating nitric oxide signal and reduces oxidative stress in the penis: A preventive treatment for priapism in sickle cell disease. FRONTIERS IN PHYSIOLOGY, v. 13, p. 12-pg., 2022-09-13. (17/08122-9, 19/17030-6, 19/18886-1)

SILVA, FABIO HENRIQUE; FERTRIN, KLEBER YOTSUMOTO; ALEXANDRE, EDUARDO COSTA; CALMASINI, FABIANO BERALDI; FRANCO-PENTEADO, CARLA FERNANDA; COSTA, FERNANDO FERREIRA. Impairment of Nitric Oxide Pathway by Intravascular Hemolysis Plays a Major Role in Mice Esophageal Hypercontractility: Reversion by Soluble Guanylyl Cyclase Stimulator. Journal of Pharmacology and Experimental Therapeutics, v. 367, n. 2, p. 194-202, NOV 1 2018. (14/00984-3, 18/06243-6, 17/08122-9)

MAGRINI IACOPUCCI, ANA PAULA; PEREIRA, PAMELA DA SILVA; PEREIRA, DALILA ANDRADE; CALMASINI, FABIANO BERALDI; PITTALA, VALERIA; REIS, LEONARDO OLIVEIRA; BURNETT, ARTHUR L.; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease. FASEB JOURNAL, v. 36, n. 10, p. 9-pg., 2022-10-01. (17/08122-9, 19/18886-1)

PEREIRA, DALILA A.; CALMASINI, FABIANO B.; SILVA, FABIO H.. Heme group increases smooth muscle relaxation of mice corpus cavernosum induced by stimulation of the NO-cGMP signaling pathway: implication for priapism in sickle cell disease. JOURNAL OF TRANSLATIONAL MEDICINE, v. 21, n. SUPPL 1, p. 1-pg., 2023-01-31. (17/08122-9)

KARAKUS, SERKAN; ANELE, UZOMA A.; SILVA, FABIO H.; MUSICKI, BILJANA; BURNETT, ARTHUR L.. Urinary dysfunction in transgenic sickle cell mice: model of idiopathic overactive bladder syndrome. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 317, n. 3, p. E540-E546, SEP 2019. (18/06243-6, 17/08122-9)

PEREIRA, DALILA A.; CALMASINI, FABIANO B.; SILVA, FABIO H.. Heme group increases smooth muscle relaxation of mice corpus cavernosum induced by stimulation of the NO-cGMP signaling pathway: implication for priapism in sickle cell disease. JOURNAL OF TRANSLATIONAL MEDICINE, v. 21, p. 1-pg., 2023-01-31. (17/08122-9)

SILVA, FABIO H.; GODOY, BEATRIZ P. B.; ALEXANDRE, EDUARDO C.; CALMASINI, FABIANO B.; DOS SANTOS, JEAN L.; COSTA, FERNANDO F.. Effect of treatment with a new nitric oxide donor, a hybrid derived from resveratrol and furoxan (E)-4-(4-(4-methoxystyryl)phenoxy)-3-methyl-1,2,5-oxadiazole-2-oxide, on priapism in sickle cell mouse and nitric oxide-deficient mouse. JOURNAL OF TRANSLATIONAL MEDICINE, v. 17, n. 1, p. 1-pg., 2019-08-15. (17/08122-9, 18/06243-6)