Pharmacological characterization of probenecid in isolated organs of the lower genitourinary tract and in models of erectile and voiding dysfunction: possible repurposing of probenecid?

• Grant number: 23/12406-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2024
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Fabíola Taufic Monica Iglesias
• Grantee: Guilherme Ruiz Leonardi
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Lower urinary tract symptoms (LUTS) involve storage complications (urgency, daytime frequency, nocturia and urge incontinence), micturition (slow flow, intermittent flow, straining to urinate, terminal dribbling and dysuria), and post-micturition (feeling incomplete emptying and post-void dribbling). In Europe and North America, the prevalence of LUTS is greater than 60% in men and women over 40 years of age. In Brazil, these symptoms affect 75% of the population, also over 40 years of age, with rates of 69% in men and 82% in women. The impact of LUTS is broad and significant, leading to impairments in social, sexual, and financial quality of life. Furthermore, it has been observed in preclinical and clinical trials that LUTS exhibit a strong correlation with erectile dysfunction, with an estimated 70% of men with LUTS experiencing associated erectile dysfunction. Drug repurposing is a strategy that aims to redirect already approved medications for clinical use, exploring new therapeutic indications. This strategy requires less time and funding as many pharmacokinetic and toxicological information in animals and humans is already available. In this project, the focus is on the uricosuric agent probenecid, which, in addition to having well-known mechanisms such as the inhibition of multidrug resistance proteins (MRPs), activation of the transient receptor potential V2 cation channel (TRPV2), and inhibition of organic anion transporters (OATs), has recently been identified as a new antagonist of pannexin-1. Pannexin-1 is highly expressed in the bladder urothelium and indirectly participates in detrusor overactivity. Based on this information, our hypothesis is that probenecid acts by promoting relaxation of the smooth muscle in the bladder, corpus cavernosum, and prostate, through the activation of the GCs-GMPc pathway and/or inhibition of the action of extracellular ATP on P2X receptors. Therefore, probenecid may act as an agent that inhibits the mechanisms of erectile dysfunction and hypercontractility in benign prostatic hyperplasia and overactive bladder. Additionally, probenecid may potentiate the effects of tadalafil, a phosphodiesterase type-5 (PDE-5) inhibitor, in the relaxation of the prostate and corpus cavernosum in animal models of erectile and prostatic dysfunction. With this in mind, our objective is to perform the pharmacological characterization of probenecid in isolated organs of the lower genitourinary tract (bladder, prostate, and corpus cavernosum) in rodents and non-rodents. Additionally, we aim to evaluate the effect of probenecid on isolated organs of the lower genitourinary tract in animal models of erectile and prostatic dysfunction, with or without the presence of tadalafil.