This study evaluated the time-course changes in bladder and external urinary sphincter (EUS) activity as well as the expression of mechanosensitive channels in lumbosacral dorsal root ganglia (DRG) after spinal cord injury (SCI). Female C57BL/6N mice in the SCI group underwent transection of the Th8/9 spinal cord. Spinal intact mice and SCI mice at 2, 4 and 6 weeks post SCI were evaluated by single-filling cystometry and EUS-electromyography (EMG). In another set of mice, the bladder and L6-S1 DRG were harvested for protein and mRNA analyses. In SCI mice, non-voiding contractions was confirmed at 2 weeks post-SCI, and did not increase over time to 6 weeks. In 2-weeks SCI mice, EUS-EMG measurements revealed detrusor-sphincter dyssynergia (DSD), but periodic EMG reductions during bladder contraction were hardly observed. At 4 weeks, SCI mice showed increases of EMG activity reduction time with increased voiding efficiency (VE). At 6 weeks, SCI mice exhibited a further increase in EMG reduction time. RT-PCR of L6-S1 DRG showed increased mRNA levels of TRPV1 and ASIC1-3 in SCI mice with a decrease of ASIC2-3 at 6 weeks compared to 4 weeks whereas Piezo2 showed a slow increase at 6 weeks. Protein assay showed the SCI-induced overexpression of bladder BDNF with a time-dependent decrease post SCI. These results indicate that detrusor overactivity is established in the early phase whereas DSD is completed later at 4 weeks with an improvement at 6 weeks post SCI, and that mechanosensitive channels may be involved in the time-dependent changes.

Aims We examined the time course of urodynamic changes and the effect of the short or long‐term inhibition of brain‐derived neurotrophic factor (BDNF) from the early phase after spinal cord injury (SCI) in mice. Methods The spinal cord of female C57BL/6N mice was completely transected. We examined filling cystometry and bladder BDNF levels at 10, 20, and 30 days after SCI, with an additional day‐5 measurement of BDNF. In a separate group of mice, anti‐BDNF antibody (Ab) (10 µg/kg/h) was subcutaneously administered using osmotic pumps from day 3 after SCI, and single‐filling cystometry was performed at 10 and 30 days (7 and 27 days of treatment, respectively) after SCI. Results Compared to spinal intact mice, bladder mucosal BDNF was increased at each time point after SCI with the maximal level at day 5 after SCI. Voiding efficiency was lower at each time point after SCI than that of spinal intact mice. The number of non‐voiding contractions (NVC) during bladder filling was gradually increased with time. In both 10‐ and 30‐day SCI groups treated with anti‐BDNF Ab, voiding efficiency was improved, and the duration of notch‐like intravesical pressure reductions during voiding bladder contractions was prolonged. The number of NVC was significantly decreased only in 30‐day SCI mice with 27‐day anti‐BDNF treatment. Conclusions Overexpression of BDNF is associated with the deterioration of voiding efficiency after SCI. The early‐started, long‐term inhibition of BDNF improved voiding dysfunction and was also effective to reduce the later‐phase development of detrusor overactivity after SCI.

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.

Abbreviations & Acronyms Actb = b actin ATF3 = activating transcription factor 3 BPH = benign prostatic hyperplasia CMG = cystometrogram DO = detrusor overactivity DRG = dorsal root ganglia iNOS = inducible nitric oxide synthase LUTD = lower urinary tract dysfunction MP = micturition pressure mRNA = messenger RNA NVC = nonvoiding contraction OAB = overactive bladder PCR = polymerase chain reaction PVR = postvoid residual urine SCI = spinal cord injury SI = spinal intact TRPA1 = transient receptor potential cation channel subfamily A member 1 TRPV1 = transient receptor potential cation channel subfamily V member 1