Naoki Yoshimura

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (440)1443.48 Total impact

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    ABSTRACT: Purpose: Glycine is an inhibitory neurotransmitter in the central nervous system. So far, two types of glycine transporters (GlyTs), GlyT-1 and GlyT-2, have been cloned. The aim of this study is to investigate the effects of a selective GlyT-1 inhibitor that can increase endogenous glycine concentration on the micturition reflex in urethane-anesthetized rats. Methods: Continuous cystometrograms (0.04 ml/min) were performed in female Sprague-Dawley rats (232-265 g) under urethane anesthesia. After stable micturition cycles were established, ALX5407, a selective GlyT-1 inhibitor, was administered intrathecally or intracerebroventricularly to evaluate changes in bladder activity. Cystometric parameters were recorded and compared before and after drug administration. Results: Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) increased intercontraction intervals at doses of 3 μg or higher in a dose-dependent fashion. Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) also increased pressure threshold at doses of 3 μg or higher in a dose-dependent fashion. However, when ALX5407 (1, 3, 10 and 30 μg) was administered intracerebroventricularly, there were no significant changes in intercontraction intervals, pressure threshold, maximum voiding pressure or baseline pressure or post-void residual urine volume at any doses tested. Conclusion: The results of our study indicate that GlyT-1 plays an important role in the modulation of micturition. Furthermore, these findings indicate that in urethane-anesthetized rats suppression of GlyT-1 can inhibit the micturition reflex at the spinal cord level. Thus, GlyT-1 could be a potential target for the treatment of bladder dysfunction such as overactive bladder.
    No preview · Article · Feb 2016 · International Urology and Nephrology
  • Mahendra Kashyap · Subrata Pore · Naoki Yoshimura · Pradeep Tyagi
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    ABSTRACT: Aims: It is known that bladder exposure to noxious stimuli elicits nerve growth factor (NGF) expression with region wise differences. Here, we investigated the effect of bladder distension (cystometry) and bladder wall injection of NGF antisense oligonucleotide (ODN) together as well as separately on spontaneous (constitutive) expression of NGF and its cognate p75 neurotrophin receptor (p75NTR). Method: Under isoflurane anesthesia, either 15μg of protamine sulfate (vehicle) alone or complexed with 1.5μg of NGF antisense or scrambled ODN was injected (10μL) at 4 sites in bladder wall of 24 adult female Sprague-Dawley rats and 6 rats were left untreated (n=30). Under urethane anesthesia, cystometry (CMG) was performed in treated and control rats. Fluorescent ODN and NGF/p75NTR expression was localized in harvested tissue. Key findings: Complexation of ODN with protamine was essential for the retention of ODN in bladder tissue as the uncomplexed ODN was untraceable after injection. Bladder distension from CMG raised the expression of NGF and p75NTR relative to CMG naïve rats. The groups treated with vehicle, scrambled and antisense ODN were indistinct with regard to CMG parameters, but the intense immunoreactivity of NGF and p75NTR seen in the vehicle and scrambled ODN groups was reduced following treatment with NGF antisense. Significance: The constitutive expression of NGF and p75NTR is responsive to bladder distension and administration of NGF antisense. Complexation with protamine reduces the clearance of ODN and demonstrates the potential of ODN nanoparticles as an option for reducing the inducible NGF expression in OAB patients following intradetrusor injection.
    No preview · Article · Feb 2016 · Life sciences
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    ABSTRACT: In order to clarify the lower urinary tract function in mice, we compared bladder and urethral activity between rats and mice with or without spinal cord injury (SCI). Female Sprague-Dawley rats and C57BL/6N mice were divided into 5 groups; (1) spinal intact (SI)-rats, (2) SI-mice, (3) pudendal nerve transection (PNT)-SI-mice, (4) spinal cord injury (SCI)-rats and (5) SCI-mice. Continuous cystometry (CMG) and external urethral sphincter (EUS)-electromyogram (EMG) analyses were conducted under an awake, restrained condition. During voiding bladder contractions, SI-animals exhibited EUS bursting with alternating active and silent periods, which, in rats but not mice, coincided with small amplitude intravesical pressure oscillations in CMG recordings. In SI-mice with bursting-like EUS activity, the duration of active periods was significantly shorter by 46% (32 ± 5 ms) compared to SI-rats (59 ± 9 ms). In PNT-SI-mice, there were no significant differences in any of cystometric parameters compared to SI-mice. In SCI-rats, fluid elimination from the urethra and the EUS bursting occurred during small amplitude intravesical pressure oscillations. However, SCI-mice did not exhibit clear EUS bursting activity or intravesical pressure oscillations but rather exhibited intermittent voiding with slow large amplitude reductions in intravesical pressure, which occurred during periods of reduced EUS activity. These results indicate that EUS pumping activity is essential for generating efficient voiding in rats with or without spinal cord injury. However, EUS bursting activity is not required for efficient voiding in SI-mice and is not re-emerged in SCI-mice, in which inefficient voiding occurs during periods of reduced tonic EUS activity.
    No preview · Article · Jan 2016 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: Purpose: Pelvic organ cross sensitization is considered to contribute to overlapping symptoms in CPPS. Overexpression of NGF in the bladder is reportedly involved in the symptom development of BPS/IC patients. This study examined whether a reduction of overexpressed NGF in the bladder by intravesical treatment with liposome and OND conjugates ameliorates bladder hypersensitivity in a rat colitis model. Materials and methods: Adult female rats were divided into; (a) a control group, (b) a colitis-OND group with intracolonic TNBS enema and intravesical liposomal-OND treatments, (c) a colitis-saline group with intracolonic TNBS and intravesical saline treatments, (d) a sham-OND group with intravesical liposomal-OND treatment without colitis and (e) a sham-saline group with intravesical saline treatment without colitis. Liposomes conjugated with NGF antisense OND or saline solution were instilled into the bladder, and 24 hours later, colitis was induced by TNBS enema. Effects of NGF antisense treatment were evaluated by pain behavior, cystometry, molecular analyses and immunohistochemistry 10 days after TNBS treatment. Results: In colitis-OND rats, the NGF antisense treatment ameliorated pain behavior, and decreased a reduction in intercontraction intervals in response to acetic acid stimulation as well as NGF expression in the bladder mucosa, which were all enhanced in colitis-saline rats compared to sham rats. Conclusions: NGF overexpression in the bladder mucosa and bladder hypersensitivity induced after colitis were reduced by intravesical application of liposomal OND targeting NGF, suggesting that the local anti-NGF therapy could be effective for the treatment of bladder symptoms in CPPS.
    No preview · Article · Jan 2016 · The Journal of urology
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    ABSTRACT: Purpose: To examine the functional role of endogenous IGF-1 in the recovery phase of SUI induced by simulated childbirth trauma using an IGF-1 receptor inhibitor. Methods: Simulated birth trauma was induced by vaginal distension (VD) in female SD rats. An IGF-1 receptor antagonist, JB-1 (10 and 100μg/kg/day) or vehicle was continuously delivered from 1 day before VD for 7 days using subcutaneous osmotic pumps. At 7, 14 and 21 days after VD, the effect of JB-1 treatment was examined by functional analyses (leak point pressure; LPP, urethral baseline pressure; UBP and urethral responses during passive increments in intravesical pressure) and molecular analyses in urethral tissues (phosphorylation of Akt, apoptotic changes and peripheral nerve density using Western blotting and immunohistochemistry). Results: In functional analyses, vehicle-treated VD rats had significantly reduced LPP, UBP and urethral responses after 7 days, which recovered to the normal level 14 and 21 days after VD. However, in the JB-1 treated VD group, LPP, UBP and urethral responses were still significantly reduced at 21 days after VD. In molecular analyses, JB-1 treatment increased apoptotic cells, induced a significant reduction of phosphorylated Akt, and prolonged the decrease of peripheral nerve density in urethral tissues. Conclusions: Suppression of endogenous IGF-1 activity delayed the recovery from SUI induced by simulated childbirth trauma in rats. Thus, IGF-1 is likely to be an important endogenous mediator for the functional recovery from childbirth-related SUI, suggesting that IGF-1 could be an effective target for the treatment of SUI in women.
    No preview · Article · Jan 2016 · The Journal of urology
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    ABSTRACT: Stress exacerbates symptoms of bladder dysfunction including overactive bladder and bladder pain syndrome, but the underlying mechanisms are unknown. Bombesin-like peptides and bombesin receptor type 1 and 2 (BB1/BB2) in the brain have been implicated in the mediation/integration of stress responses. In this study, we examined effects of centrally administered bombesin on micturition, focusing on their dependence on (1) the sympatho-adrenomedullary system, a representative mechanism activated by stress exposure, and (2) brain BB receptors, in urethane-anesthetized (1.0-1.2 g/kg, i.p.) male rats. Intracerebroventricularly (i.c.v.) administered bombesin significantly shortened intercontraction intervals (ICI) at both doses (0.1 and 1 nmol/animal) without affecting maximal voiding pressure. Bombesin at 1 nmol induced significant increments of plasma noradrenaline and adrenaline levels, which were both abolished by acute bilateral adrenalectomy (ADX). On the other hand, ADX showed no effects on the bombesin-induced shortening of ICI. Much lower doses of bombesin (0.01 and 0.03 nmol/animal, i.c.v.) dose-dependently shortened ICI. Pretreatment with either a BB1 receptor antagonist BIM-23127 (D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH2; 3 nmol/animal, i.c.v.) or a BB2 receptor antagonist BEA (H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; 3 nmol/animal, i.c.v.) respectively suppressed the BB (0.03 nmol/animal, i.c.v.)-induced shortening of ICI, while each antagonist by itself (1 and 3 nmol/animal, i.c.v.) had no significant effects on ICI. Bombesin (0.03 nmol/animal, i.c.v.) significantly reduced voided volume per micturition and bladder capacity without affecting post-void residual volume or voiding efficiency. These results suggest that brain bombesin and BB receptors are involved in facilitation of the rat micturition reflex to induce bladder overactivity, which is independent of the sympatho-adrenomedullary outflow modulation.
    Preview · Article · Jan 2016 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: Introduction: Interstitial cystitis or bladder pain syndrome (IC/BPS) is a debilitating chronic disease characterized by suprapubic pain and lower urinary tract symptoms: however, the etiology is still unknown. Therefore, the long-lasting, effective treatments of IC/BPS are still not established, and the treatment is sometimes empirically selected depending on practitioners' experience and preference. Area covered: In this review we focus on the current treatments, ongoing clinical trials, and several potential new drugs based on the results of basic and clinical research studies. First, we discuss the potential etiologies of IC/BPS that include altered barrier lining, afferent and/or central nervous system abnormalities, possible contribution of inflammation or infection and abnormal urothelial signaling. Then, the current therapies of IC/BPS, either systemic or local, are reviewed by critical evaluation of the efficacy and shortcomings of each treatment. Finally, based on proposed etiologies of the disease, potential emerging drugs and treatments are discussed. Expert opinion: Current therapies often fail to control the symptoms of IC/BPS. Several interventions including sustained drug release and retaining techniques, and drugs that act on afferent neural pathways are emerging and may be promising. In addition, phenotyping of IC/BPS patients based on cystoscopic findings (e.g., Hunner vs. non-Hunner lesion) or patients' symptoms would be important for further investigation of IC/BPS etiology and the evaluation of efficacy of new treatments.
    No preview · Article · Nov 2015 · Expert Opinion on Emerging Drugs
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    ABSTRACT: Objective: To investigate the time dependent changes in expression of cytokines that characterizes the spontaneous recovery of reflex voiding after spinal cord injury (SCI). SCI is known to reorganize the neural circuitry of micturition reflex after injury. Methods: Under isoflurane anesthesia, spinal cord of 18 adult female Sprague-Dawley rats was completely transected at the Th9/10 level. Awake cystometry was performed on controls and 6 SCI animals at each time point of 4, 8 and 12 weeks and bladder was then harvested for analysis of 29 proteins Millipore kit or ELISA. Prophylactic dose of ampicillin 100mg/kg was administered periodically to all SCI animals. Results: Spontaneous recovery of voiding after SCI at 12 weeks was evident from increased intercontractile interval and voiding efficiency during cystometry. Expression of pro-inflammatory interleukins (IL-1α and IL-1β, IL-2 IL-5, IL-6, IL-18, TNF- α) and CXC chemokines (CXCL1, CXCL2, CXCL10), CX3CL1 and CCL2 showed significant elevation at 4 and 8 weeks with slight decrease at 12 weeks. In contrast, expression of anti-inflammatory interleukin IL-10 and neuroprotective factors, BDNF,CXCL-5 and Leptin was elevated at 8 and 12 weeks (p<0.05). In contrast, expression of CCL3, CCL5 and growth factors VEGF, NGF, EGF, G-CSF, GM-CSF did not show any significant temporal change after SCI. Conclusions: Spontaneous recovery of reflex voiding at 12 weeks was marked by increased endogenous expression of anti-inflammatory cytokine IL-10 and neuroprotective factors BDNF, CXCL-5 and leptin, which suggests that pharmacological suppression of inflammation, can hasten the emergence of reflex voiding after SCI.
    No preview · Article · Nov 2015 · Urology
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    ABSTRACT: Purpose: The present study examined dynamic changes in neural activity of the anterior cingulate cortex (ACC) and the midbrain periaqueductal gray (PAG) during the micturition reflex in a Parkinson's disease (PD) model as well as the effects of direct stimulation of the ACC on the micturition reflex. Materials and methods: Electrodes were inserted into the ACC or the PAG, and the effects of intravenous (i.v.) administration of ZM24138 (ZM: adenosine A2A receptor antagonist) on the pelvic nerve evoked field potentials were examined. The effect of electrical stimulation of the ACC was also examined. Results: PD rats showed bladder overactivity evidenced by a significant decrease in intercontraction intervals (ICI) compared with sham rats. I.v. administration of ZM increased ICI in both groups with the inhibitory effects being greater in PD; and dose-dependently increased the amplitude of evoked potentials in the ACC of PD rats but not in sham rats. I.v. administration of ZM reduced the evoked potential amplitude in the PAG of both groups with the inhibitory effects being greater in PD vs. sham rats. Electrical stimulation of the ACC significantly increased ICI. Conclusions: These results suggest that ACC neurons have an inhibitory role in bladder control because neural activity in the ACC was significantly increased along with suppression of bladder overactivity after ZM administration in the PD model, and the stimulation of the ACC inhibited the micturition reflex. Understanding the roles of the ACC in the modulation of micturition could provide further insights into the pathophysiology of OAB.
    No preview · Article · Nov 2015 · The Journal of urology
  • Pradeep Tyagi · Mahendra Kashyap · Harvey Hensley · Naoki Yoshimura
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    ABSTRACT: Introduction: Intravesical therapy is a valuable option in the clinical management of urinary tract disorders such as interstitial cystitis/ painful bladder syndrome (IC/PBS) and refractory overactive bladder. This review will cover the latest advances in this field using polymer and liposomes as delivery platform for drugs, protein and nucleic acids. Areas covered: This review summarizes the significance of intravesical therapy for lower urinary tract disorders. The recent advancement of liposomes as a drug delivery platform for botulinum toxin, tacrolimus and small interfering RNA is discussed. The importance of polymers forming indwelling devices and hydrogels are also discussed, where all preparations improved efficacy parameters in rodent models. Clinical experience of treating IC/PBS with indwelling devices and liposomes are summarized and preclinical evidence about the downregulation of target gene expression in rodent bladder with liposomes complexed with siRNA is also reviewed. Expert opinion: There have been several advances in the field of intravesical therapy for improving clinical outcomes. One of the most promising research avenues is the repurposing of drugs, given previously by other routes of administration, such as tacrolimus. Intravesical therapy also opens up novel therapeutic targets with improved efficacy and safety for underactive bladder.
    No preview · Article · Oct 2015 · Expert Opinion on Drug Delivery
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    ABSTRACT: Objectives To investigate the role of noradrenergic pathways in the urethral continence reflex during abdominal compression in rats. Methods Under urethane anesthesia, urethral baseline pressure (UBP) and urethral pressure response (UPR) during momentary abdominal compression using a 100 g weight was measured using a transurethral microtransducer-tipped catheter placed at the middle urethra in Sprague-Dawley female rats. Following intravenous (i.v.) application of hexamethonium or -bungarotoxin to block urethral smooth or striated muscle function, respectively, the effects of terazosin, an (1)-adrenoceptor (AR) antagonist (0.3 mg/kg, i.v.), medetomidine, an (2)-AR agonist (0.3 mg/kg, i.v.) or nisoxetine, a norepinephrine reuptake inhibitor (1 mg/kg, i.v.) followed by terazosin on UBP and UPR were examined. ResultsAfter hexamethonium pretreatment, terazosin did not alter UBP or UPR, whereas medetomidine significantly decreased UPR by 28% without UBP changes. Nisoxetine significantly increased UPR by 64%, which was eliminated by terazosin, but UBP was not altered by nisoxetine. After -bungarotoxin pretreatment, UBP and UPR were significantly decreased by terazosin or medetomidine. Nisoxetine induced significant increases in UBP and UPR by 16 and 15%, respectively, which were antagonized by terazosin. Conclusion These results suggest that: the baseline activity and reflex contraction of urethral smooth muscle are decreased by (1)-AR inhibition or (2)-AR stimulation; the reflex contraction of urethral striated muscle is decreased by (2)-AR stimulation, but not by (1)-AR inhibition; and nisoxetine increases baseline and reflex activity of smooth muscle in addition to striated muscle reflex activity by (1)-AR stimulation. These findings will be useful to understand nerve-mediated urethral closure mechanisms.
    No preview · Article · Sep 2015 · Lower urinary tract symptoms
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    ABSTRACT: To examine alterations in expression of angiotensin II type 1 receptors (AT1R) which induce organ tissue remodeling, angiotensin II type 2 receptors (AT2R) which protect against it, and related molecules in the bladder of matured rats with bladder dysfunction. Female SD rats of three different ages were used: 8 weeks old (8W; n = 5), 9 months old (9M; n = 5), and 15 months old (15M; n = 5). After cystometry, the expression levels of AT1R, connexin43 (Cx43), MAP kinase (MAPK), collagen1, AT2R, PPAR-γ, adiponectin (Adipo), and adiponectin receptor (Adipo-R) were investigated in the bladder. Pressure threshold, post-void residual volume and the number of non-voiding contractions were significantly increased in 15M versus 8W rats (P < 0.01). Maximum voiding pressure was significantly decreased in 15M versus 8W rats (P < 0.05). There was no significant difference in CMG parameters between 8W and 9M rats. In the bladder, the mRNA expression of AT1R, Cx43, MAPK, collagen 1, AT2R, PPAR-γ, Adipo, and Adipo-R were significantly higher in 15M than in 8W rats. The relative expression ratio of AT1R protein against AT2R protein in the mucosa and detrusor was significantly increased in 15M versus 8W rats. These results indicate that matured rats exhibit not only bladder overactivity but also impaired voiding, which are associated with upregulation of AT1R. The upregulation of AT2R also may play a significant role in the suppressing of AT1R induced remodelling. However, because AT1R upregulation is more dominant than AT2R increases, AT2R activation may not be sufficient to suppress AT1R stimulation in matured rats. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Aug 2015 · Neurourology and Urodynamics
  • N. Wada · K. Kadekawa · T. Majima · T. Shimizu · P. Tyagi · H. Kakizaki · N. Yoshimura

    No preview · Conference Paper · Aug 2015
  • Z Jallah · R Liang · A Feola · W Barone · S Palcsey · SD Abramowitch · N Yoshimura · P Moalli
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    ABSTRACT: To evaluate the impact of prolapse meshes on vaginal smooth muscle structure (VaSM) and function, and to evaluate these outcomes in the context of the mechanical and textile properties of the mesh. Three months following the implantation of three polypropylene prolapse meshes with distinct textile and mechanical properties, mesh tissue explants were evaluated for smooth muscle contraction, innervation, receptor function, and innervation density. Magee-Womens Research Institute at the University of Pittsburgh. Thirty-four parous rhesus macaques of similar age, parity, and pelvic organ prolapse quantification (POP–Q) scores. Macaques were implanted with mesh via sacrocolpopexy. The impact of Gynemesh™ PS (Ethicon; n = 7), Restorelle® (Coloplast; n = 7), UltraPro™ parallel and UltraPro™ perpendicular (Ethicon; n = 6 and 7, respectively) were compared with sham-operated controls (n = 7). Outcomes were analysed by Kruskal–Wallis ANOVA, Mann–Whitney U–tests and multiple regression analysis (P < 0.05). Vaginal tissue explants were evaluated for the maximum contractile force generated following muscle, nerve, and receptor stimulation, and for peripheral nerve density. Muscle myofibre, nerve, and receptor-mediated contractions were negatively affected by mesh only in the grafted region (P < 0.001, P = 0.002, and P = 0.008, respectively), whereas cholinergic and adrenergic nerve densities were affected in the grafted (P = 0.090 and P = 0.008, respectively) and non-grafted (P = 0.009 and P = 0.005, respectively) regions. The impact varied by mesh property, as mesh stiffness was a significant predictor of the negative affect on muscle function and nerve density (P < 0.001 and P = 0.013, respectively), whereas mesh and weight was a predictor of receptor function (P < 0.001). Mesh has an overall negative impact on VaSM, and the effects are a function of mesh properties, most notably, mesh stiffness. Prolapse mesh affects vaginal smooth muscle.
    No preview · Article · Aug 2015 · BJOG An International Journal of Obstetrics & Gynaecology

  • No preview · Conference Paper · Aug 2015

  • No preview · Conference Paper · Aug 2015
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    ABSTRACT: Increased afferent excitability has been proposed as an important pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder (OAB). In this study, we investigated whether herpes simplex virus (HSV) vectors encoding poreless TRPV1, in which the segment in C terminus of TRPV1 receptor is deleted, suppress bladder overactivity and pain behavior using a rat model of chemical cystitis. Replication-defective HSV vectors encoding poreless TRPV1 were injected into the bladder wall of adult female Sprague-Dawley rats. Additionally, vHG vectors were injected as control. Cystometry (CMG) under urethane anesthesia was performed 1 week after viral injection to evaluate bladder overactivity induced by resiniferatoxin (RTx, a TRPV1 agonist). RTx-induced nociceptive behavior such as licking (lower abdominal licking) and freezing (motionless head-turning) was observed 2 weeks after viral injection. GFP expression in L4/L6/S1 dorsal root ganglia and the bladder as well as c-Fos positive cells in the L6 spinal cord dorsal horn were also evaluated 2 weeks after viral injection. In CMG, the poreless TRPV1 vector-treated group showed a significantly smaller reduction in intercontraction intervals and voided volume after RTx infusion than the vHG-treated control group. The number of the RTx-induced freezing events was significantly decreased in the poreless TRPV1 group than in the vHG group whereas there was no significant difference of the number of RTx-induced licking events between groups. The number of c-Fos positive cells in the DCM and SPN regions of the L6 spinal dorsal horn was significantly smaller in the poreless TRPV1 group than in the vHG group. Our results indicated that HSV vector-mediated gene delivery of poreless TRPV1 had a therapeutic effect on TRPV1-mediated bladder overactivity and pain behavior. Thus, the HSV vector mediated gene therapy targeting TRPV1 receptors could be a novel modality for the treatment of OAB and/or hypersensitive bladder disorders such as IC/BPS.
    No preview · Article · Jul 2015 · Human gene therapy
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    ABSTRACT: Objective: The second messenger cAMP is involved in both β3 adrenoceptor (β3-AR) mediated detrusor relaxation and the kinetics of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Here we characterized the effect HCN channel activation and possible interaction with β3-AR in bladder. Materials and methods: Bladder tissues from Sprague-Dawley rats and Human organ donors were obtained for studying species-specific expression of HCN channels by real-time qPCR and Western Blot. Effect of β3-agonist on rat bladder strips (0.5 × 0.5 × 7 mm in size) was studied during activation and blockade of HCN channels by Lamotrigine and ZD7288, respectively. Results: Expression of all four genes encoding for HCN channels (HCN1-4) was detected separately in bladder mucosa and detrusor from human and rat bladders. Species based differences were evident from relatively higher expression of HCN4 isoform in human bladder and that of HCN1 in rat bladder. Western blot confirmed the findings at mRNA level. Cumulative application β3-AR agonist CL316,243 produced a concentration dependent decrease in resting tension of rat bladder strips expressed as integral of mechanical activity. Pre-incubation of HCN channel blocker ZD 7288 opposed the relaxant effect of CL316,243, whereas co-administration of lamotrigine with CL316,243 at equal molar concentrations caused an additive decrease in resting tension. Cumulative addition of ZD7288 and lamotrigine in absence of CL316,243 showed opposing effects on detrusor contractility. Conclusions: Species-specific differences were noted in expression of HCN channels in bladder. Opposing effects ZD7288 and Lamotrigine in the action of β3-AR agonist demonstrate possible functional interaction of HCN channels and β3-AR in detrusor contractility.
    Full-text · Article · Jul 2015
  • William C de Groat · Naoki Yoshimura
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    ABSTRACT: Functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. Neural control of micturition is organized as a hierarchic system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily during the early postnatal period, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults cause re-emergence of involuntary micturition, leading to urinary incontinence. The mechanisms underlying these pathologic changes are discussed. © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · May 2015 · Handbook of Clinical Neurology
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    ABSTRACT: Background There is mounting evidence to support the role of inflammation in benign prostate hyperplasia (BPH), and a recent study reported expression of inflammasome derived cytokine IL-18 in prostate biopsy of BPH patients. Here we examined the expression of inflammasome-derived cytokines and activation of nucleotide-binding oligomerization domain-like receptor with pyrin domain protein 1 (NLRP) 1 inflammasome in a rat model of prostatic inflammation relevant to BPH. Methods Prostatic inflammation was experimentally induced in three-month-old male Sprague–Dawley rats by intraprostatic injection (50 μL) of either 5 % formalin or saline (sham) into the ventral lobes of prostate. 7 days later, prostate and bladder tissue was harvested for analysis of inflammasome by Western blot, immunohistochemistry and downstream cytokine production by Milliplex. Results Expression of interleukins, CXC and CC chemokines were elevated 2-15 fold in formalin injected prostate relative to sham. Significant expression of NLRP1 inflammasome components and caspase-1 in prostate were associated with significant elevation of pro and cleaved forms of IL-1β (25.50 ± 1.16 vs 3.05 ± 0.65 pg/mg of protein) and IL-18 (1646.15 ± 182.61 vs 304.67 ± 103.95 pg/mg of protein). Relative to prostate tissue, the cytokine expression in bladder tissue was much lower and did not involve inflammasome activation. Conclusions Significant upregulation of NLRP1, caspase-1 and downstream cytokines (IL-18 and IL-1β) suggests that a NLRP1 inflammasome is assembled and activated in prostate tissue of this rat model. Recapitulation of findings from human BPH specimens suggests that the inflammasome may perpetuate the inflammatory state associated with BPH. Further clarification of these pathways may offer innovative therapeutic targets for BPH-related inflammation.
    Full-text · Article · May 2015 · Journal of Inflammation

Publication Stats

9k Citations
1,443.48 Total Impact Points


  • 1994-2016
    • University of Pittsburgh
      • • Department of Pharmacology and Chemical Biology
      • • Department of Urology
      • • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2014
    • Kaohsiung Municipal Ta-Tung Hospital, Taiwan
      Kao-hsiung-shih, Kaohsiung, Taiwan
  • 2013
    • Tottori University
      • Division of Urology
      Tottori, Tottori-ken, Japan
  • 2006
    • Chang Gung University
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2003
    • Pittsburg State University
      Питсбург, Kansas, United States
  • 2001
    • Chang Gung Memorial Hospital
      T’ai-pei, Taipei, Taiwan
  • 1987-2001
    • Kyoto University
      • • Department of Urology
      • • Department of Pharmacology
      Kioto, Kyōto, Japan
  • 1991
    • Rakuwakai Otowa Hospital
      Kioto, Kyōto, Japan