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Objectives: To examine the effect of intrathecal (i.t.) serotonin (5‐hydroxytryptamine) 5‐HT7 agonist administration on voiding function in the urethane‐anesthetised rat, and the change in 5‐HT7 receptor (5‐HT7R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). Materials and methods: In all, 32 female Sprague–Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5‐HT7R‐selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. Results: LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1–30 μg/kg) induced significant dose‐dependent increases in micturition volume, voiding efficiency, number of high‐frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non‐voiding contractions. The 5‐HT7R antagonist, SB‐269970 (10 μg/kg), partially reversed LP44‐induced changes. Using PRV retrograde tracing and immunofluorescence, 5‐HT7Rs were found in the L6–S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5‐HT7Rs in the ventral L6–S1 spinal cord in SCI rats. Conclusion: A 5‐HT7R agonist, given i.t., improved voiding efficiency in urethane‐anesthetised SCI rats, and the 5‐HT7R was significantly up‐regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5‐HT7R could be a target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aim: To investigate the value of repeat botulinum toxin A (BTX‐A) injections in patients with neurogenic detrusor overactivity (NDO). Methods: We searched the PubMed, EMBASE, and EBSCO databases for articles published until June 2016. Studies that reported the efficacy and safety of repeat BTX‐A injections for adult patients with NDO were eligible. The effect size for each outcome was calculated as the standardized mean difference ± standard error and 95% confidence interval, and was graded as small, >0.2; moderate, >0.5; or large, >0.8. The outcomes included maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), reflex volume (RV), bladder compliance (BC), quality of life (QOL), and injection interval. Descriptive reviews were performed for urinary incontinence (UI) and adverse events (AEs). Results: Eighteen studies involving 1533 patients whose level of evidence ranged from 3 to 4 were included in this study. We noted non‐significant changes in MCC, MDP, RV, and BC between the first and last injections. Patients who had received ≤4 injections were found to have stable QOL improvements after the first and last injections, whereas patients who had received ≥5 injections were found to have a significant decrease in QOL after the last injection. No significant differences in injection intervals were noted after repeat BTX‐A injections, and the repeat injection failure rate was low. Conclusion: Our study demonstrated that repeat BTX‐A injections allow sustained improvements in patients with NDO. The rate of AEs was stable and low. However, additional high‐quality, large‐scale, and long‐term trials are necessary to establish the efficacy and safety of ≥5 repeat BTX‐A injections. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5‐HT)2A/2C receptor agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropanehydrochloride (DOI), and to discuss whether the mechanism can be ascribed to 5‐HT2A and 5‐HT 2C receptor upregulation in lumbosacral cord motoneurons. Materials and Methods: Female Sprague–Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5‐HT2A and ‐2C receptors in the lumbosacral cord were also investigated using immunohistochemical staining and Western blot analysis. Results: Compared with NC rats, the SCI rats had higher bladder capacity and post‐void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5‐HT2A and ‐2C receptors were upregulated in lumbosacral cord motoneurons. Conclusion: In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5‐HT2A and ‐2C receptor upregulation in lumbosacral cord motoneurons controlling EUS activity. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice. We used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 μg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neuron to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K+ (K A) and sustained delayed rectifier-type K+ (K DR) currents were significantly reduced by SCI. The reduction of K A , but not K DR , current density was reversed by the treatment with p38 MAPK inhibitor. P38 MAPK plays an important role in hyperexcitability of capsaicin-sensitive bladder afferent neurons due to the reduction in K A channel activity in SCI mice. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) as the leading cause of urination disorder is still a refractory disease, and there have no satisfied drugs or treatment protocols yet. With identifying excessive Zn 2+ , inflammation, and oxidative stress as the etiology of aberrant hyperplasia, an injectable sodium alginate (SA) and glycyrrhizic acid (GA)-interconnected hydrogels (SAGA) featuring Zn 2+ -triggered in situ gelation are developed to load lonidamine for reprogramming prostate microenvironment and treating BPH. Herein, SAGA hydrogels can crosslink with Zn 2+ in BPH via coordination chelation and switch free Zn 2+ to bound ones, consequently alleviating Zn 2+ -arisen inflammation and glycolysis. Beyond capturing Zn 2+ , GA with intrinsic immunoregulatory property can also alleviate local inflammation and scavenge reactive oxygen species (ROS). Intriguingly, Zn 2+ chelation-bridged interconnection in SAGA enhances its mechanical property and regulates the degradation rate to enable continuous lonidamine release, favoring hyperplastic acini apoptosis and further inhibiting glycolysis. These multiple actions cooperatively reprogram BPH microenvironment to alleviate characteristic symptoms of BPH and shrink prostate. RNA sequencing reveals that chemotaxis, glycolysis, and tumor necrosis factor (TNF) inflammation-related pathways associated with M1-like phenotype polarization are discerned as the action rationales of such endogenous Zn 2+ -triggered in situ hydrogels, providing a candidate avenue to treat BPH., (© 2023 Wiley-VCH GmbH.)

Lower urinary tract (LUT) dysfunction is the most common complication of diabetes mellitus (DM). An involvement of the 5-HT 2A receptor in spinal micturition control has been demonstrated in urethane anaesthetized DM rats in which i.v. administration of the 5-HT 2A/2C receptor agonist 2,5-methoxy-4-iodoamphetamine (DOI), stimulated high frequency oscillations (HFOs) and improved micturition. However, the mechanisms involved in these effects are not completely understood. The present work showed that 5-HT 2A and -2C receptors were upregulated in lumbosacral cord motoneurons, and the number of serotonergic paraneurons were downregulated in the urethra in DM group. The importance of the downregulation of urethral paraneurons in DM remains to be elucidated but may be related to the reduced urethral sensation caused by the disease. We suggest that targets of 5-HT receptor agonists for improvement of voiding function may be found both in the LUT and lumbosacral spinal cord., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT 7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT 7 receptor (5-HT 7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI)., Materials and Methods: In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT 7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot., Results: LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30 μg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT 7 R antagonist, SB-269970 (10 μg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT 7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT 7 Rs in the ventral L6-S1 spinal cord in SCI rats., Conclusion: A 5-HT 7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT 7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT 7 R could be a target for therapeutic interventions., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Objectives: This study aimed to investigate the effects of ketanserin on micturition mediated via the 5-HT 2A receptor in the motoneuron nucleus of the Lumbosacral cord, as reflected in high frequency oscillations (HFOs) of intravesical pressure and the external urethral sphincter electromyogram (EUS-EMG) in anesthetized male rats. METHODS：: Male Sprague-Dawley rats were used. Cystometry and EUS-EMG were performed in all rats under urethane anesthesia to examine the variations after successive intrathecal (i.t.) administration of various doses of ketanserin into the lumbosacral cord. Immunofluorescence staining and Western blotting were made to observe the distribution of 5-HT2 A and -2C receptors in the lumbosacral cord motor neurons., Results: Compared to the controls, ketanserin-treated rats showed a declined trend of dose-dependent manner in the HFOs, in accordance with the variation of EUS-EMG, while decreased micturition volume, voiding efficiency, and increased post-void residual volume was only observed at the dose of 0.1 mg/kg. The effects of ketanserin on the HFO and EUS-EMG activity were partially or completely reversed by the 5-HT 2A/2C receptor agonist, DOI. Meanwhile, immunofluorescence staining and Western blot analysis showed that immunoreactivity of 5-HT 2A receptor was higher than that of 5-HT 2C, labeling in the lumbosacral cord motoneurons., Conclusions: The intrathecally administrated 5-HT 2A receptor antagonist ketanserin can weaken the EUS bursting activity, decrease HFOs, and reduce voiding efficiency as dose dependently. The effects of ketanserin on micturition may be mainly mediated via the 5-HT 2A receptors in the motoneuron nucleus of the lumbosacral cord., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5-HT) 2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropanehydrochloride (DOI), and to discuss whether the mechanism can be ascribed to 5-HT 2A and 5-HT 2C receptor upregulation in lumbosacral cord motoneurons., Materials and Methods: Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HT 2A and - 2C receptors in the lumbosacral cord were also investigated using immunohistochemical staining and Western blot analysis., Results: Compared with NC rats, the SCI rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HT 2A and - 2C receptors were upregulated in lumbosacral cord motoneurons., Conclusion: In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT 2A and - 2C receptor upregulation in lumbosacral cord motoneurons controlling EUS activity., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)