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Purpose We systematically reviewed preclinical and clinical studies on bladder chemodenervation with onabotulinumtoxin A to highlight current limitations and future drug delivery approaches. Materials and Methods We identified peer reviewed basic and clinical research studies of onabotulinumtoxin A in the treatment of neurogenic bladder and refractory idiopathic overactive bladder published between March 2000 and March 2016. Paired investigators independently screened 125 English language articles to identify controlled studies on onabotulinumtoxin A administration in the MEDLINE® database and abstracts presented at annual American Urological Association meetings. The review yielded an evidence base of more than 50 articles relevant to the approach of injection-free onabotulinumtoxin A chemodenervation. Results The efficacy and safety of intradetrusor injection of onabotulinumtoxin A for the treatment of overactive bladder are sensitive to injection volume and depth, and this issue has motivated researchers to study injection-free modes of drug delivery into the bladder. Urothelial denudation with protamine sulfate or dimethyl sulfoxide, liposome encapsulated onabotulinumtoxin A and other physical approaches are being studied to increase toxin permeability and avoid intradetrusor injections. Liposome encapsulated onabotulinumtoxin A enhances toxin activity while reducing its toxin degradation. The safety and efficacy of liposome encapsulated onabotulinumtoxin A were tested in a multicenter, placebo controlled study. Although this treatment successfully reduced urinary frequency and urgency, it did not significantly reduce urgency urinary incontinence episodes. Conclusions Intradetrusor injection of onabotulinumtoxin A is a safe and effective treatment as reported in several large multicenter, randomized controlled trials. Injection of the toxin into the bladder wall impairs afferent and efferent nerves, but injection-free drug delivery approaches only impair the bladder afferent nerves. Further studies are needed to develop better drug delivery platforms that overcome the drawbacks of intradetrusor injection, increase patient acceptance and reduce treatment costs. [ABSTRACT FROM AUTHOR]

Purpose In the current study we examined dynamic changes in neural activity of the anterior cingulate cortex and the midbrain periaqueductal gray during the micturition reflex in a Parkinson’s disease model as well as the effects of direct stimulation of the anterior cingulate cortex on the micturition reflex. Materials and Methods Electrodes were inserted in the anterior cingulate cortex or the periaqueductal gray. The effects of intravenous administration of the adenosine A2A receptor antagonist ZM24138 on pelvic nerve evoked field potentials were examined. The effect of electrical stimulation of the anterior cingulate cortex was also examined. Results Rats with Parkinson’s disease showed bladder overactivity as evidenced by a significant decrease in the intercontraction interval compared with sham operated rats. Intravenous administration of ZM24138 increased the intercontraction interval in both groups with the inhibitory effects greater in rats with Parkinson’s disease. It dose dependently increased the amplitude of evoked potentials in the anterior cingulate cortex of rats with Parkinson’s disease but not in sham operated rats. Intravenous administration of ZM24138 decreased evoked potential amplitude in the periaqueductal gray of both groups with the inhibitory effects greater in Parkinson’s disease vs sham operated rats. Electrical stimulation of the anterior cingulate cortex significantly increased the intercontraction interval. Conclusions These results suggest that anterior cingulate cortex neurons have an inhibitory role in bladder control. Neural activity in the anterior cingulate cortex was significantly increased along with suppression of bladder overactivity after ZM241385 administration in the Parkinson’s disease model and the stimulation of the anterior cingulate cortex inhibited the micturition reflex. Understanding the roles of the anterior cingulate cortex in the modulation of micturition could provide further insights into the pathophysiology of overactive bladder. [ABSTRACT FROM AUTHOR]

Purpose: We examined the effect of IGF-1 in a rat model of stress urinary incontinence induced by simulated childbirth trauma. Materials and Methods: Simulated birth trauma was induced by vaginal distension in female Sprague Dawley® rats. Four, 7, 14 and 28 days after distension we performed functional assessment by measuring leak point pressure, urethral baseline pressure and the urethral response during a passive increment in intravesical pressure. The expression of IGF-1 and IGF1R mRNA and protein in damaged tissues was examined by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. Thereafter hrIGF-1 (50 and 150 μg/kg per day) was continuously delivered from 1 day before distension using subcutaneous osmotic pumps. Four and 7 days after distension the effect of hrIGF-1 treatment was examined by functional analysis of leak point pressure, urethral baseline pressure and the urethral response as well as Western blot and histological analysis. Results: After 4 and 7 days rats with vaginal distension had significantly decreased leak point pressure, urethral baseline pressure and urethral responses. IGF-1 and IGF1R mRNA and protein levels were significantly increased in urethral and pudendal nerves 4 and 7 days after distension. IGF-1 treated groups showed significant improvement in leak point pressure, urethral baseline pressure and urethral responses 4 and 7 days after distension. Moreover, IGF-1 treatment increased Akt phosphorylation and induced cellular proliferation and antiapoptotic effects in the urethra. Conclusions: IGF-1 treatment accelerated recovery from stress urinary incontinence induced by simulated childbirth trauma in association with activation of the Akt signal transduction pathway in rats. This suggests that IGF-1 has therapeutic potential for stress urinary incontinence in women. [ABSTRACT FROM AUTHOR]

Purpose: Nerve growth factor over expression in the bladder has a role in overactive bladder symptoms via the mediation of functional changes in bladder afferent path- ways. We studied whether blocking nerve growth factor over expression in bladder urothelium by a sequence specific gene silencing mechanism would suppress bladder overactivity and chemokine expression induced by acetic acid. Materials and Methods: Female Sprague-Dawley@ rats anesthetized with isoflurane TM were instilled with 0.5 ml saline, scrambled or TYE 563 labeled antisense ohgonu otide targeting nerve growth factor (12/μM) alone or complexed with cationic liposomes for 30 minutes. The efficacy of nerve growth factor antisense treatments for acetic acid induced bladder overactivity was assessed by cystometry. Bladder nerve growth factor expression levels and cellular distribution were quantified by immunofluorescence stain- ing and enzyme-linked immunosorbent assay. Effects on bladder chemokine expression were measured by Luminex@ xMA_P@ analysis. Results: Liposomes were needed for bladder uptake of ohgonucleotide, as seen by the absence of bright red TYE 563 fuorescence in rats instilled with oligonucleotide alone. At 24 hours afar liposome-oligonucleotide treatment baseline bladder activity during sa- line infusion was indistinct in the sham and ant/sense treated groups with a mean +_ SEM intercontraction interval of 348 ± 55 and 390 ± 120 seconds, respectively. Acetic acid induced bladder overactivity was shown by a decrease in the intercontraction interval to a mean of 33.2% ± 4.0% of baseline in sham treated rats. However, the reduction was blunted to a mean of 75.8% ± 3.4% of baseline in rats treated with liposomal antisense oligonucleotide (p <0.05). Acetic acid induced increased nerve growth factor in the urothehum of sham treated rats, which was decreased by ant/sense treatment, as shown by enzyme-linked immunosorbent assay and reduced nerve growth factor immunoreactivity in the urothelium. Increased nerve growth factor in bladder tissue was associated with sICAM-1, sE-selectin, CXCL-IO and 1, leptin, MCP-1 and vascular endothelial growth factor over expression, which was significantly decreased by nerve growth factor antisense treatment (p <0.01). Conclusions: Acetic acid induced bladder overactivity is associated with nerve growth factor over expression in the urothelium and with chemokine up-regula- tion. Treatment with liposomal antisense suppresses bladder overactivity, and nerve growth factor and chemokine expression. Local suppression of nerve growth factor in the bladder could be an attractive approach for overactive bladder. It would avoid the systemic side effects that may be associated with nonspecific blockade of nerve growth factor expression. [ABSTRACT FROM AUTHOR]

Purpose: A new animal model in which to concurrently evaluate bladder function and nociceptive behavior was developed using freely moving, noncatheterized, conscious rats to assess the nociceptive behavior responses induced by intravesical instillation of resiniferatoxin (Sigma®) and its relationship with bladder dysfunction. Materials and Methods: In female Sprague-Dawley rats resiniferatoxin (0, 0.3 and 3 μM) was instilled via a catheter that was temporarily inserted into the bladder through the urethra. After removing the catheter the incidence of nociceptive behavior (lower abdominal licking and freezing) was scored. Voided urine was collected continuously to measure bladder capacity. In some rats the pudendal nerves were transected bilaterally to eliminate the activation of urethral afferents by resiniferatoxin. Results: Intravesical instillation of resiniferatoxin induced decreased bladder capacity and increased nociceptive behaviors, such as licking and freezing, which were blocked by the transient receptor potential vanilloid receptor 1 antagonist BCTC (Biomol™). In rats with pudendal nerve transection the early phase of resiniferatoxin induced licking was decreased without affecting the resiniferatoxin induced decrease in bladder capacity and late phase licking behavior. Resiniferatoxin induced late phase licking in the water unloaded group was observed to a lesser extent than in the water loaded diuresis group. Conclusions: The intravesical instillation of resiniferatoxin, which decreases bladder capacity, acts by at least 3 distinct mechanisms to induce licking behavior, including 1) an immediate response mediated by the activation of urethral afferents in the pudendal nerve, 2) a late response evoked by the direct stimulation of C-fiber afferents in the bladder and 3) gradual facilitation of the response elicited by the bladder wall distention induced by rapid bladder filling. [Copyright &y& Elsevier]