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 vibegrontreated 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.

Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin

“…The vast majority of the analyzed reports, 74%, use spinal cord injury as an NDO model ( Figure 2 B). From these publications, 59% report complete transection of thoracic segments to induce SCI [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 38 , 39 , 43 , 44 , 46 , 48 , 49 , 50 , 55 , 57 , 62 , 63 ], followed by spinal contusion (13%). The use of spinal hemisections was less frequent (10%) [ 42 , 47 , 52 ], as were spinal compressions (8%) [ 32 , 36 , 54 , 56 ] and other SCI methods (10%) [ 41 , 51 , 53 , 58 ] ( Figure 3 ).…”

“…Most of the studies reporting urodynamic recordings used awake cystometry as the recording method (37%) [ 31 , 32 , 33 , 34 , 35 , 38 , 39 , 42 , 46 , 47 , 48 , 52 , 56 , 59 , 63 , 68 , 70 , 71 ]. Cystometry under anesthesia represented 26% of studies, with 16% using urethane delivered via subcutaneous [ 26 , 27 , 28 , 37 , 41 , 43 , 51 ] or intraperitoneal injection [ 57 ], 8% using zolotyl [ 53 , 58 , 61 , 74 ], and 2% referring the use of chloral hydrate as anesthetic [ 54 ].…”

Implantation of adipose-derived mesenchymal stem cell sheets promotes axonal regeneration and restores bladder function after spinal cord injury

“…Previous studies have demonstrated that SCI induces bladder remodeling associated with tissue fibrosis, which may adversely affect smooth muscle function and the bladder capacity to micturition properly, resulting in a low voiding efficiency and reduced compliance [ 34 , 35 ]. In this study, compared with fibrosis of the bladder wall in the SCI group, the ADSC group showed normal morphology of the bladder wall and reduced tissue fibrosis as demonstrated by downregulation of type 1 collagen.…”

Video‐urodynamic effects of vibegron, a new selective β3‐adrenoceptor agonist, on antimuscarinic‐resistant neurogenic bladder dysfunction in patients with spina bifida

“…25 Furthermore, Gotoh et al reported that vibegron could indirectly suppress C-fiber bladder afferent activity and reduce DO by acting on both nerves and muscles in mice with spinal cord injury. 26 Nantel et al reported that the b3-adrenoceptor is resistant to long-term desensitization, which might have promoted the sustained efficacy of vibegron. 27 These findings suggest that vibegron could be an alternative treatment option for antimuscarinic-resistant neurogenic bladder dysfunction.…”