Effects of a new β3-adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury.

Abstract

AIMS:

To examine vibegron effects on lower urinary tract dysfunction (LUTD) in mice with spinal cord injury (SCI).

METHODS:

Female mice underwent Th8-9 spinal cord transection and were orally administered vehicle or vibegron after SCI. We evaluated urodynamic parameters at 4 weeks after SCI with or without vibegron. Fibrosis- and ischemia-related messenger RNA (mRNA) and protein levels of collagen and elastin were measured in bladders of vehicle- and vibegron-treated SCI mice, and spinal intact mice.

RESULTS:

Non-voiding contractions (NVCs) were significantly fewer (15.3 ± 8.9 vs 29.7 ± 11.4 contractions; P < .05) and the time to the first NVC was significantly longer (1488.0 ± 409.5 vs 782.7 ± 399.7 seconds; P < .01) in vibegron-treated SCI mice vs vehicle-treated SCI mice. mRNAs levels of collagen types 1 and 3, transforming growth factor-β1 (TGF-β1), and hypoxia-inducible factor-1α (HIF-1α) were significantly upregulated in vehicle-treated SCI mice compared with spinal intact and vibegron-treated SCI mice (Col 1: 3.5 vs 1.0 and 2.0-fold; P < .01 and P < .05, Col 3: 2.1 vs 1.0 and 1.2-fold; P < .01 and P < .05, TGF-β1: 1.2 vs 1.0 and 0.9-fold; P < .05 and P < .05, HIF-1α: 1.4 vs 1.0 and 1.0-fold; P < .05 and P < .01). Total collagen and elastin protein levels in vehicle- and vibegron-treated SCI mice did not differ.

CONCLUSIONS:

Vibegron reduced NVCs, delayed the first NVC, and improved collagen types 1 and 3, TGF-β1, and HIF-1α mRNA expression in SCI mice. Vibegron might be effective for SCI-induced LUTD.

• Authors: Daisuke Gotoh, Nobutaka Shimizu, Naoki Wada, Katsumi Kadekawa, Tetsuichi Saito, Shinsuke Mizoguchi, Yosuke Morizawa, Shunta Hori, Makito Miyake, Kazumasa Torimoto, William C de Groat, Kiyohide Fujimoto, Naoki Yoshimura
• Journal: Neurourology and urodynamics (Neurourol Urodyn) Vol. 39 Issue 8 Pg. 2120-2127 (11 2020) ISSN: 1520-6777 [Electronic] United States
• PMID: 32816344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Adrenergic beta-3 Receptor Agonists
• N-(4-((5-(hydroxy(phenyl)methyl)pyrrolidin-2-yl)methyl)phenyl)-4-oxo-4,6,7,8-tetrahydropyrrolo(1,2-a)pyrimidine-6-carboxamide
• Pyrimidinones
• Pyrrolidines

Topics

• Adrenergic beta-3 Receptor Agonists (pharmacology, therapeutic use)
• Animals
• Disease Models, Animal
• Female
• Mice
• Pyrimidinones (pharmacology, therapeutic use)
• Pyrrolidines (pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Spinal Cord Injuries (complications, physiopathology)
• Treatment Outcome
• Urinary Bladder, Neurogenic (drug therapy, etiology, physiopathology)
• Urination (drug effects)
• Urodynamics (drug effects)