Dynamic renal scintigraphy (DRS) is an imaging modality of choice for diagnosing the structural and functional obstruction in the urinary tract after intravenous injection of radiotracers such as Tc-99 m diethylenetriaminepentaacetic acid (DTPA). While upper urinary tract obstruction can prolong the elimination half-life > 20 min of Tc-99 m DTPA, false-positive diagnosis of upper urinary tract obstruction can also result from lower renal excretion of Tc-99 m DTPA due to reduced urinary production in dehydrated individuals, and reduced renal excretion increases the reabsorption of Tc-99 m DTPA from the bladder. Here, we dissected the purported cause for the false-positive results of prolonged elimination half-life > 20 min of Tc-99 m DTPA during dynamic image acquisition for DRS before bladder emptying. The prevalent view in nuclear medicine implicates back pressure of bladder as the purported cause of false positive results and ignores the contribution of kidney recycling Tc-99 m DTPA reabsorbed from bladder. Here, we distilled published clinical evidence to draw a mechanistic insight into the role of Tc-99 m DTPA reabsorption from the bladder in DRS.

The etiology of IC/BPS is multifactorial; thus, pathophysiology-based phenotyping is needed for tailored treatments of IC/BPS patients. In this regard, it is now generally agreed that, when focusing on inflammatory responses in the bladder mucosa, IC/BPS is divided into two major phenotypes. One is "interstitial cystitis (IC)," which is a chronic inflammatory disorder with Hunner lesions, and the other is "bladder pain syndrome (BPS)," in which inflammatory changes are minimal without Hunner lesions. However, as another important pathophysiological change in the IC/BPS bladder, angiogenetic responses including overexpression of angiogenic growth factors, such as platelet-derived endothelial cell growth factor (PD-ECGF), vascular endothelial growth factor (VEGF), and CD31 (platelet endothelial cell adhesion molecule; PECAM-1), have been shown to correlate with symptom severity in Hunner-type IC and non-Hunner IC/BPS patients. In addition, previous studies in IC/BPS patients showed that glomerulations or mucosal bleeding during hydrodistension occur due to the rupture of bladder mucosal capillary vessels in association with PD-ECGF and VEGF overexpression. Furthermore, upregulation of angiogenic factors and their signaling pathways has been detected in animal models of IC/BPS induced by bladder inflammation or psychological stress. Thus, angiogenic factor overexpression and immature microvessel formation in the bladder mucosa could be another important diagnostic criterion in addition to the inflammatory status for further phenotyping of IC/BPS.

BACKGROUND:Benign prostatic hyperplasia (BPH) is the most common disease in aging males. BPH growth is androgen-dependent, and it appears that androgens preferentially stimulate the growth of BPH as compared to normal prostate. The mechanism of preferential androgen stimulation of BPH growth is not clear. Our previous studies suggest that primary BPH stromal cells, but not the paired normal adjacent prostate (NAP) stromal cells from the same patients, could stimulate prostatic epithelial cell proliferation in 3D co-culture. However, whether androgen regulation of prostatic stromal cells is altered in BPH nodules is not clear. METHODS:Paired BPH and NAP primary stromal cells were prepared from the same patients. Early passage paired BPH and NAP primary cells were treated with androgens and/or antiandrogens for RNA-seq analysis. RNA-seq data were analyzed using principal component analysis (PCA) and functional enrichment analysis. Conditioned medium of the paired BPH and NAP primary cells in the presence or absence of androgens were used in three-dimensional (3D) culture of benign prostatic epithelial cells. RESULTS:RNA-seq data analysis suggests that androgen-induced gene expression in BPH primary stromal cells is heightened compared to paired NAP stromal cells. AR activation in BPH stromal cells appears to enhance cellular motility, vascular and extracellular matrix remodeling, and paracrine signaling, while simultaneously modulating cell cycle and metabolic processes. Compared to regular BPH stromal conditioned medium, conditioned medium of androgen-stimulated BPH stromal cells further enhanced prostatic epithelial cell proliferation in 3D culture. In contrast, medium of NAP stromal cell culture conditioned in the presence of androgen had no significant effect on prostatic epithelial cell proliferation in 3D culture. CONCLUSIONS:Our findings suggest that androgen stimulation of prostatic epithelial cell growth via paracrine prostatic stromal signaling is enhanced in BPH and is associated with heightened androgen-responsiveness of BPH stromal cells.

PURPOSE:To investigate the adenosine receptor (AR) mechanism underlying bladder outlet obstruction (BOO)-related bladder dysfunction, we examined the expression level of AR subtypes in bladder tissues, and the effects of AR subtypes A2B & A3 modulation on bladder activity using male BOO rats, and Dahl rats with A2B receptor deletion. MATERIALS AND METHODS:BOO was induced by partial ligation of the proximal urethra in male Sprague-Dawley rats. At 4 weeks after BOO, conscious cystometrograms (CMG) were performed with the urethral ligature being intact. The effects of AR A3 agonist (2CL-IB-MECA) and AR A3 antagonist (MRS3777) were examined by intravesical administration. Furthermore, we examined the difference of bladder function of AR subtypes between AR A2B knockout (A2B-KO) and wild-type groups of male Dahl rats. mRNA levels of AR subtypes in bladder tissues were also analyzed. RESULTS:BOO versus sham rats showed heavier bladder weights, higher contraction amplitudes, and increased numbers of non-voiding contractions (NVCs) during the filling phase. In the bladder mucosa - but not the detrusor - of BOO versus sham rats, mRNA expression levels of A2A and A3 AR were significantly increased, while A2B levels were significantly decreased. In BOO rats, an A3 antagonist (MRS 3777; 10 and 100 μM) had no effect on CMG parameters. However, a high dose of an A3 agonist (2CL-IB-MECA; 100 μM) significantly increased NVCs (p = 0.0034), an effect that was blocked by the A3 antagonist. Additionally, compared to wild-type rats, A2B-KO rats showed a significant increase in the number of NVCs (p = 0.0039). CONCLUSIONS:A2B AR down-regulation in BOO rats and A2B deletion in Dahl rats could contribute to the development of bladder overactivity. Moreover, a high-level of exogenous activation of A3 ARs might exacerbate bladder overactivity in BOO.

This study evaluated the effects of the imidazoline I2 receptor (I2R) agonist 2-(2-benzofuranyl)-2-imidazoline (2BFI) on lower urinary tract dysfunction (LUTD) in a mouse spinal cord injury (SCI) model. Female mice were divided into three groups: spinal intact (SI), SCI with vehicle, and SCI with 2BFI beginning 2 wk postinjury. SCI was induced by complete Th8-9 spinal transection. Four weeks after SCI, conscious cystometrograms (CMG) and external urethral sphincter (EUS) electromyography (EMG) were recorded. L6-S1 dorsal root ganglia (DRG) were collected for qPCR analysis of TRPV1, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS). In a separate group of animals, intrathecal (i.t.) 2BFI was tested during CMG/EMG in SCI. Organ bath studies assessed 2BFI-induced relaxation in bladder strips precontracted with KCl or carbachol. SCI mice showed increased nonvoiding contractions (NVCs) and reduced voiding efficiency versus SI. 2BFI significantly decreased NVCs, improved voiding efficiency, and prolonged EUS relaxation, evident as reduced EMG activity compared with vehicle. SCI-induced upregulation of TRPV1, TNF-α, and iNOS in DRG was significantly attenuated by 2BFI. I.t. 2BFI reduced residual urine and NVCs and increased EUS relaxation in SCI mice. In organ baths, 2BFI produced significant relaxation of precontracted bladder strips from both SI and SCI mice. I2R activation in the lumbosacral spinal cord and bladder may provide an effective therapeutic strategy for SCI-induced LUTD.NEW & NOTEWORTHY This study shows that selective activation of the imidazoline-2 receptor improves both detrusor overactivity and detrusor-sphincter dyssynergia after spinal cord injury. Systemic and intrathecal administration of 2BFI produced coordinated actions in the spinal cord and lower urinary tract, including enhanced relaxation of the external urethral sphincter, reduced inflammation mediated by C-fiber afferents, and direct relaxation of bladder smooth muscle, indicating a promising therapeutic target.

Purpose To investigate the effectiveness of acotiamide on lower urinary tract dysfunction by using a rat model of neurogenic underactive bladder induced through pelvic nerve crush (PNC) injury. Methods Bilateral PNC injuries were performed on 8-week-old female Sprague-Dawley rats (PNC group); the sham surgery group was used as control (control group). Two weeks after surgery, awake cystometrography (CMG) was performed, and acotiamide (10 or 100 mg/kg) was subcutaneously administered to the control and PNC groups. Subsequently, CMG parameter values obtained before and after treatment were compared. Results In baseline CMG, compared to control group, PNC group revealed statistically significant elevations in the intercontraction intervals (ICIs), number of nonvoiding contractions, baseline pressure, threshold pressure, bladder capacity, voided volumes, and postvoid residual. However, contraction amplitudes and voiding efficiency were significantly decreased. In the control group, compared with the baseline values, 10-mg/kg acotiamide resulted in statistically significant elevations in contraction amplitudes. Treatment with 100-mg/kg acotiamide led to statistically significant elevations in contraction amplitudes and decreases in ICI and bladder volume. In the PNC group, there were no statistically significant changes noted in CMG parameters after treatment with 10-mg/kg acotiamide (n=6). Compared with the baseline values, the administration of 100-mg/kg acotiamide significantly decreased ICI (1,025±186 seconds vs. 578±161 seconds; P=0.012), bladder capacity (1,841±323 µL vs. 871±174 µL, respectively; P=0.0059) and postvoid residual (223±46 µL vs. 44±22 µL, respectively; P=0.023), and increased contraction amplitudes (22.09±1.76 cm H2O vs. 43.84±6.87 cm H2O, respectively; P=0.012) and voiding efficiency (0.87±0.02 vs. 0.94±0.03, respectively; P=0.029). Conclusions Acotiamide showed effectiveness in the treatment of underactive bladder, possibly through activation of bladder afferent and detrusor activities.

AIMS:We examined the role of subtypes of adenosine receptors in bladder dysfunction and changes in the adenosine receptor expression in the bladder using male rats with partial bladder outlet obstruction (BOO). METHODS:In Sprague-Dawley rats (male 8-weeks old), BOO was produced by a partial ligation of the urethra along a metal rod of a 1.2 mm outer diameter. Control rats underwent sham operation. Awake cystometrograms (CMG) were first recorded during saline instillation, and then an adenosine A1 receptor agonist (CCPA, 4.1 μM), an adenosine A2A antagonist (ZM241385, 15 μM), or inosine (1 mM) were applied intravesically in sham and BOO rats. In addition, mRNA levels of adenosine receptor subtypes in the bladder wall were measured using RT-PCR. Histological studies of bladder specimen were also performed. RESULTS:Weights of BOO bladders were significantly (p < 0.0001) larger compared with sham bladders. In CMG, a number of non-voiding contractions (NVCs), bladder contraction amplitudes during voiding, bladder capacity, and post-void residual (PVR) were significantly (p < 0.001) increased compared with sham rats. Voiding efficiency (VE) was significantly (p < 0.001) reduced in BOO versus sham rats. Intravesical application of CCPA or inosine did not induce statistically significant effects on CMG parameters in BOO rats. Yet, ZM241385 induced a significant (p = 0.040) reduction in NVCs of BOO rats. mRNA levels of adenosine A2A and A3 receptors were significantly (p < 0.0001 and p = 0.0145, respectively) upregulated in the BOO bladder mucosa, whereas adenosine A2B receptors showed a significant (p < 0.0001) reduction in the BOO bladder mucosa compared with sham bladders. Histologically, we found the thickened detrusor muscle layer in BOO versus sham rats. CONCLUSIONS:The male rat model of BOO seems to be suitable for exploring urethral obstruction-related bladder dysfunction at the compensated phase. In addition, the adenosine A2A receptor subtype would be a potential target for the treatment of male BOO patients with bladder overactivity. CLINICAL TRIAL REGISTRATION:A clinical trial registration is not required as this study reported the basic research data using animal models.

The high compliance of the urinary bladder during filling is essential for its proper function, enabling it to accommodate significant volumetric increases with minimal rise in transmural pressure. This study aimed to elucidate the physical mechanisms underlying this phenomenon by analyzing the ex vivo filling process in rat from a fully voided state to complete distension, without preconditioning, using three complementary imaging modalities. High-resolution micro-CT at 10.8 [Formula: see text]m resolution was used to generate detailed 3D reconstructions of the bladder lumen, revealing an average 62-fold increase in bladder volume during filling. Pressure-volume studies of whole bladder delineated three mechanical filling regimes: an initial high-compliance phase, a transitional phase, and a final high-pressure phase. While prior studies conjectured small mucosal rugae (∼450 [Formula: see text]m) are responsible for the high compliance phase, multiphoton microscopy (MPM) of the dome of the voided bladder revealed large folds in voided bladders an order of magnitude larger than these rugae. Bladder imaging during the inflation process demonstrated flattening of these large scale folds in the initial high compliance phase. The 3D reconstructions of the bladder lumen in the filled and voided state revealed a high voiding efficiency of 97.13% ± 2.42%. The MPM imaging results suggest the large scale folds in the dome enable this high voiding fraction by driving urine toward the bladder outlet. These insights are vital for developing realistic computational models of bladder micturition and understanding changes to bladder function due to pathological conditions such as bladder outlet obstruction and age-related dysfunction.

This study aimed to characterize the time-dependent changes in lower urinary tract function in a rat model of partial bladder outlet obstruction (BOO) using noninvasive techniques, including uroflowmetry and ultrasound imaging. Eight-week-old male rats underwent partial ligation of the urethra to induce BOO. Voiding behavior was assessed preoperatively and at 1, 2, and 4 weeks postoperatively using metabolic cages. Urine flow rate was calculated based on changes in voided volume over time. Average flow rate, maximum flow rate, and voiding time were derived from these metabolic cage data. Bladder capacity and wall thickness were evaluated by high-resolution ultrasonography. Voiding frequency significantly increased at 1, 2, and 4 weeks compared to preoperative values. Mean voided volume per micturition was significantly reduced at 2 weeks. Urinary flow curves showed a sawtooth-like pattern, suggestive of external urethral sphincter bursting that is a characteristic of rat voiding. The maximum flow rate significantly decreased at 1 week postoperatively and remained reduced through 4 weeks. Mean flow rate was significantly decreased at 2 weeks, while voiding time showed a tendency to increase, although the difference was not statistically significant. Ultrasonography revealed significant increases in maximum bladder volume at 2 and 4 weeks and in anterior bladder wall thickness at 4 weeks. This study demonstrated the feasibility of noninvasively monitoring time-dependent changes in rats with BOO. These findings could be extrapolated to the pathophysiological process during the bladder compensation phase in human BOO.

Clinically accepted for treatment of chronic pain 10 kHz-frequency electric spinal cord stimulation (10 kHz-SCS) releases more power in tissue compared to conventional low-frequency (<100 Hz) stimulation due to increased duty cycle. This is equivalent to the release of more heat in a surrounding tissue, which may change the functional state of affected neural elements. In the case of SCS, plausible candidates to be affected by thermal a component of kHz-frequency electric field stimulation (kHz-FS) are dorsal column axons and neurons of the superficial layers of the dorsal horn. In this study, we tested the hypothesis that joule heat produced by kHz-FS modulates neuronal excitability. In slices of the mouse spinal cord, we monitored membrane potential and membrane input resistance in neurons of lamina II during exposure to kHz-FS. Surprisingly, we found no correlation between temperature rise and changes of membrane parameters. Furthermore, the depolarizing effect of kHz-FS was always immediate and remained persistent throughout stimulation, whereas rise of temperature was delayed for 1-2 s and reached its saturation level within the following few seconds. Thus, we concluded that the thermal component has an insignificant role in the mechanism of kHz-FS action.

Inhibitory control of external urethral sphincter motor neurons (EUS-MNs) in the spinal dorsolateral nucleus (DLN), which corresponds to a portion of Onuf's nucleus in humans, is essential for normal micturition by inducing EUS relaxation during voiding; yet synaptic mechanisms remain poorly characterized. Using neonatal mice P8-P12, we developed a slicing technique-cutting spinal cords at 150° from the coronal plane (30° from the horizontal plane in the agarose block), for maximizing EUS-MNs captured per slice. Using transgenic mice co-expressing channelrhodopsin-2 in inhibitory interneurons (VGAT-ChR2) and GFP in cholinergic neurons (ChAT-GFP), we investigated inhibitory synaptic transmission onto EUS-MNs. Optogenetic activation evoked robust inhibitory postsynaptic potentials (IPSPs), classified as sustained or transient based on temporal profiles. Pharmacology revealed that sustained IPSPs contained both glycinergic and GABAergic components, while GABAA receptors predominantly mediated transient IPSPs. Strychnine (1 μM) selectively blocked glycinergic transmission, while bicuculline (10 μM) eliminated GABAergic components. Insensitivity to glutamatergic antagonists (CNQX and AP5) confirmed purely inhibitory responses. Our findings demonstrate segregation of inhibitory inputs onto EUS-MNs, with glycinergic and GABAergic transmission contributing to sustained and transient inhibition, respectively, establishing the methodological foundation for investigating inhibitory circuit dynamics in pathological conditions such as spinal cord injury with deficient inhibitory control.

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology (MP59)1 May 2024MP59-02 IMIDAZOLINE 2 RECEPTOR ACTIVATION IMPROVES DETRUSOR OVERACTIVITY OF MICE WITH SPINAL CORD INJURY THROUGH RELAXATION OF BLADDER SMOOTH MUSCLES Mamoru Hashimoto, Kanako Matsuoka, Kang Jun Cho, Stephanie L. Daugherty, Nobutaka Shimizu, Kazutoshi Fujita, Akihide Hirayama, Hirotsugu Uemura, Sergei Karnup, and Naoki Yoshimura Mamoru HashimotoMamoru Hashimoto , Kanako MatsuokaKanako Matsuoka , Kang Jun ChoKang Jun Cho , Stephanie L. DaughertyStephanie L. Daugherty , Nobutaka ShimizuNobutaka Shimizu , Kazutoshi FujitaKazutoshi Fujita , Akihide HirayamaAkihide Hirayama , Hirotsugu UemuraHirotsugu Uemura , Sergei KarnupSergei Karnup , and Naoki YoshimuraNaoki Yoshimura View All Author Informationhttps://doi.org/10.1097/01.JU.0001009476.18935.3b.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To investigate the effects of imidazoline 2 receptor (I2R) activation on lower urinary tract dysfunction (LUTD) in mice with spinal cord injury (SCI). METHODS: C57BL/6N female mice at 9-10-weeks old were used. SCI mice underwent complete transection of the Th8-9 spinal cord. Four weeks after SCI, cystometrograms was performed under an awake condition. Two-weeks treatment with 2BFI (I2R agonist)was initiated at 2 weeks after SCI. In organ bath studies, the urinary bladder from SCI mice was cut into two longitudinal strips. Bladder body muscle strips were then mounted longitudinally in a vertical double-jacketed organ bath with 37 °C oxygenated 15 mL Krebs solution. BU224 (100 μM) (I2R antagonist) was applied to each bath 15 minutes prior to 2BFI application (1, 10, 100 μM). To induce precontraction of muscle strips, we added KCl (80 μM) or carbachol (10 μM) to each bath. We waited for 30-40 minutes after inducing precontraction before each drug was added. RESULTS: SCI mice with and without 2BFI exhibited significantly reduced voiding efficiency and an increased number of non-voiding contractions (NVC) compared with spinal intact mice. However, SCI mice with 2BFI showed better voiding efficiency and the reduced number of NVC than SCI mice without 2BFI. In organ bath studies, 2BFI induced relaxation in muscle strips precontracted with KCl or carbachol. BU224 reduced the relaxation effects of 2BFI (Figure 1). CONCLUSIONS: These results suggest that imidazoline 2 receptor activation improved detrusor overactivity evident as the NVC reduction, at least in part, by bladder smooth muscle relaxation in SCI mice. Thus, I2R could be a therapeutic target for the treatment of SCI-induced LUTD. Download PPT Source of Funding: Funding: NIH R01DK129194 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e957 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Mamoru Hashimoto More articles by this author Kanako Matsuoka More articles by this author Kang Jun Cho More articles by this author Stephanie L. Daugherty More articles by this author Nobutaka Shimizu More articles by this author Kazutoshi Fujita More articles by this author Akihide Hirayama More articles by this author Hirotsugu Uemura More articles by this author Sergei Karnup More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement PDF downloadLoading ...

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology (PD12)1 May 2024PD12-08 A RADIATION-FREE, VIRTUAL MEASUREMENT OF MOUSE BLADDER BLOOD FLOW Pradeep Tyagi, Anirban Ganguly, Lesley Foley, T. Kevin Hitchens, and Naoki Yoshimura Pradeep TyagiPradeep Tyagi , Anirban GangulyAnirban Ganguly , Lesley FoleyLesley Foley , T. Kevin HitchensT. Kevin Hitchens , and Naoki YoshimuraNaoki Yoshimura View All Author Informationhttps://doi.org/10.1097/01.JU.0001008772.30001.48.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bladder barrier function is critically dependent on high metabolic rate of mucosa, nourished by a lion's share of bladder perfusion reaching mucosa instead of muscle during storage phase. However, this skewed blood flow to mucosa is not correctly measured by most widely used method of laser Doppler because the readout is sensitive to the variable distance between probe application site and deeper artery from dome to trigone. Past studies validated the principle of deriving blood flow from the relative concentration of fluorescent microspheres in bladder wall and femoral artery of animal sacrificed post-arterial injection of microspheres (PMID: 10992421). Same principle of microspheres infusion assay guides the virtual determination of the relative concentration of injected Gadolinium chelate in bladder wall (BW) and in iliac artery from the ratio of dynamic contrast enhancement (DCE) between bladder wall and iliac artery in DCE-MRI. Hence, we posited that DCE-MRI can generate a virtual readout of bladder blood flow without collecting blood or bladder tissue. METHODS: Under isoflurane anesthesia, three months old male and female C57BL6 mice (n=6) received 0.1 mL tail vein injection of Gadobutrol at dose of 0.1 mmol/kg for T1 weighted DCE-MRI at 7T Bruker BioSpec system with repetition time/echo time of 200/5.23 milliseconds, number of excitations=1, voxel volume of 0.156×0.156×0.8 mm3 and temporal resolution of 6.5-12 s between frames. RESULTS: BW and of internal iliac artery were visible on the same 0.8 mm thick axial slice acquired with a large field of view of 2×2 cm2 and high BW perfusion rate is evident from the equivalence in time to peak (TTP) enhancement of respective time-intensity curves. Tofts modelling of DCE computed that injected Gadobutrol [30 mM] gets instantly diluted 15 fold and 75 fold to >2 mM and 0.4 mM in artery and BW, respectively. While >2 mM indexes the arterial input function of internal iliac artery with a reported blood flow rate of ∼2 mL/min (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348007/), the ratio of 0.4:2 mM indexes that the relative bladder blood flow is 25% of iliac artery, or 0.4 mL/min. CONCLUSIONS: This is a first reliable measurement of mouse bladder perfusion in a radiation-free and non-tissue destructive fashion, a method amenable to repeated measurment on same animal for quantifying the impact of outlet obstruction, infection, or inflammation and treatment on bladder blood flow. Download PPT Source of Funding: Hillman Cancer foundation, P30CA047904 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e259 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Pradeep Tyagi More articles by this author Anirban Ganguly More articles by this author Lesley Foley More articles by this author T. Kevin Hitchens More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement PDF downloadLoading ...

As opposed to classical overactive (OAB) symptoms, Parkinson disease (PD) patients often exhibit detrusor hyperreflexia and impaired contractility or underactive bladder. OAB would be more related to central nervous system dysfunction, but nerve damage in peripheral ganglia (eg, pelvic ganglia in the bladder wall) may play a mechanism of dysfunction manifesting as underactive bladder in PD. We propose a novel hypothesis regarding neurogenic urologic dysfunction in PD, suggesting a potential involvement of peripheral nervous system dysfunction in addition to central nervous system dysfunction. This hypothesis emphasizes the significance of investigating peripheral neuron damage in the urinary bladder. We hereby review the relevant neurogenic bladder dysfunction associated with PD, compare and contrast OAB and underactive bladder manifestations and dysfunction, and discuss novel considerations toward this disease with great unmet needs.

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD03)1 May 2024PD03-06 MITOCHONDRIAL COMPLEX I PROTEIN NDUFS3 IS DECREASED IN BENIGN PROSTATIC HYPERPLASIA PATIENTS TREATED WITH CELECOXIB AND/OR FINASTERIDE Chandler N. Hudson, Teresa T. Liu, Taro Igarashi, Nathalie El-Khoury, Nnamdi Ihejirika, Kelsey Paxton, Juliann Jaumotte, Rajiv Dhir, Joel B. Nelson, Donald B. DeFranco, William A. Ricke, Naoki Yoshimura, Zhou Wang, and Laura E. Pascal Chandler N. HudsonChandler N. Hudson , Teresa T. LiuTeresa T. Liu , Taro IgarashiTaro Igarashi , Nathalie El-KhouryNathalie El-Khoury , Nnamdi IhejirikaNnamdi Ihejirika , Kelsey PaxtonKelsey Paxton , Juliann JaumotteJuliann Jaumotte , Rajiv DhirRajiv Dhir , Joel B. NelsonJoel B. Nelson , Donald B. DeFrancoDonald B. DeFranco , William A. RickeWilliam A. Ricke , Naoki YoshimuraNaoki Yoshimura , Zhou WangZhou Wang , and Laura E. PascalLaura E. Pascal View All Author Informationhttps://doi.org/10.1097/01.JU.0001009388.01015.e5.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is treated with multiple medical therapies and surgical options with variable outcomes. Some of the heterogeneity in treatment efficacy may come from an incomplete understanding of their molecular and cellular impact. A decline in essential mitochondrial protein expression has been observed in BPH tissues, suggesting mitochondrial dysfunction may be a factor in BPH pathogenesis. Both finasteride and celecoxib have been associated with mitochondrial toxicity in other tissues. The objective of this study was to determine whether the BPH therapies finasteride and celecoxib might impact mitochondrial function in prostate tissues, specifically their effects on NDUFS3. METHODS: NDUFS3, E-cadherin and inflammatory cell immunostaining were performed on simple prostatectomy BPH specimens from patients naïve to androgen manipulation who were treated with celecoxib and/or finasteride for 28 days in a four-arm, phase II randomized, single-blind clinical trial. NDUFS3 and inflammatory cell staining was also conducted in a murine model of celecoxib treatment in male mice. Quantification analyses of immunostaining were performed. RESULTS: NDUFS3 was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3, and however there was no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with a decline in NDUFS3 in prostate tissues but no change in inflammatory cell infiltration. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, therapeutic targeting of BPH with celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in BPH patients. Future development of therapeutic strategies improving mitochondrial function may improve the efficacy of celecoxib and/or finasteride in BPH patients. Source of Funding: This work was funded in part by NIH grants K01 AG059899 from NIA to TL; U54 DK104310, R01 DK131175, and R01 DK127081 from NIDDK to WAR; U54 DK112079 and R56 DK107492 from NIDDK to ZW; and CAIRIBU Convergence Award to LEP from NIDDK. This project also used the Pitt Biospecimen Core and was supported in part by award P30CA047904 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e78 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Chandler N. Hudson More articles by this author Teresa T. Liu More articles by this author Taro Igarashi More articles by this author Nathalie El-Khoury More articles by this author Nnamdi Ihejirika More articles by this author Kelsey Paxton More articles by this author Juliann Jaumotte More articles by this author Rajiv Dhir More articles by this author Joel B. Nelson More articles by this author Donald B. DeFranco More articles by this author William A. Ricke More articles by this author Naoki Yoshimura More articles by this author Zhou Wang More articles by this author Laura E. Pascal More articles by this author Expand All Advertisement PDF downloadLoading ...