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Chueh KS, Juan TJ, Lu JH, Wu BN, Lin RJ, Mao JW, Lin HY, Chuang SM, Chang CY, Shen MC, Sun TW, Juan YS. Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Detrusor Hyperactivity with Impaired Contractility via Transient Potential Vanilloid Channels: A Rat Model for Ovarian Hormone Deficiency. Int J Mol Sci 2024; 25:4927. [PMID: 38732143 PMCID: PMC11084446 DOI: 10.3390/ijms25094927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
This study explores low-intensity extracorporeal shock wave therapy (LiESWT)'s efficacy in alleviating detrusor hyperactivity with impaired contractility (DHIC) induced by ovarian hormone deficiency (OHD) in ovariectomized rats. The rats were categorized into the following four groups: sham group; OVX group, subjected to bilateral ovariectomy (OVX) for 12 months to induce OHD; OVX + SW4 group, underwent OHD for 12 months followed by 4 weeks of weekly LiESWT; and OVX + SW8 group, underwent OHD for 12 months followed by 8 weeks of weekly LiESWT. Cystometrogram studies and voiding behavior tracing were used to identify the symptoms of DHIC. Muscle strip contractility was evaluated through electrical-field, carbachol, ATP, and KCl stimulations. Western blot and immunofluorescence analyses were performed to assess the expressions of various markers related to bladder dysfunction. The OVX rats exhibited significant bladder deterioration and overactivity, alleviated by LiESWT. LiESWT modified transient receptor potential vanilloid (TRPV) channel expression, regulating calcium concentration and enhancing bladder capacity. It also elevated endoplasmic reticulum (ER) stress proteins, influencing ER-related Ca2+ channels and receptors to modulate detrusor muscle contractility. OHD after 12 months led to neuronal degeneration and reduced TRPV1 and TRPV4 channel activation. LiESWT demonstrated potential in enhancing angiogenic remodeling, neurogenesis, and receptor response, ameliorating DHIC via TRPV channels and cellular signaling in the OHD-induced DHIC rat model.
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Affiliation(s)
- Kuang-Shun Chueh
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.-S.C.); (C.-Y.C.)
- Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80661, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (S.-M.C.); (M.-C.S.); (T.-W.S.)
| | - Tai-Jui Juan
- Department of Medicine, National Defense Medical College, Taipei 11490, Taiwan; (T.-J.J.); (J.-W.M.)
| | - Jian-He Lu
- Emerging Compounds Research Center, Department of Environmental Science and Engineering, College of Engineering, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Bin-Nan Wu
- Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Rong-Jyh Lin
- Department of Parasitology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jing-Wen Mao
- Department of Medicine, National Defense Medical College, Taipei 11490, Taiwan; (T.-J.J.); (J.-W.M.)
| | - Hung-Yu Lin
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan;
- Division of Urology, Department of Surgery, E-Da Cancer Hospital, Kaohsiung 82445, Taiwan
- Division of Urology, Department of Surgery, E-Da Hospital, Kaohsiung 824005, Taiwan
| | - Shu-Mien Chuang
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (S.-M.C.); (M.-C.S.); (T.-W.S.)
| | - Chao-Yuan Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.-S.C.); (C.-Y.C.)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Mei-Chen Shen
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (S.-M.C.); (M.-C.S.); (T.-W.S.)
| | - Ting-Wei Sun
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (S.-M.C.); (M.-C.S.); (T.-W.S.)
| | - Yung-Shun Juan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.-S.C.); (C.-Y.C.)
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (S.-M.C.); (M.-C.S.); (T.-W.S.)
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Doelman AW, Streijger F, Majerus SJA, Damaser MS, Kwon BK. Assessing Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury: Animal Models in Preclinical Neuro-Urology Research. Biomedicines 2023; 11:1539. [PMID: 37371634 PMCID: PMC10294962 DOI: 10.3390/biomedicines11061539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/20/2023] [Accepted: 05/21/2023] [Indexed: 06/29/2023] Open
Abstract
Neurogenic bladder dysfunction is a condition that affects both bladder storage and voiding function and remains one of the leading causes of morbidity after spinal cord injury (SCI). The vast majority of individuals with severe SCI develop neurogenic lower urinary tract dysfunction (NLUTD), with symptoms ranging from neurogenic detrusor overactivity, detrusor sphincter dyssynergia, or sphincter underactivity depending on the location and extent of the spinal lesion. Animal models are critical to our fundamental understanding of lower urinary tract function and its dysfunction after SCI, in addition to providing a platform for the assessment of potential therapies. Given the need to develop and evaluate novel assessment tools, as well as therapeutic approaches in animal models of SCI prior to human translation, urodynamics assessment techniques have been implemented to measure NLUTD function in a variety of animals, including rats, mice, cats, dogs and pigs. In this narrative review, we summarize the literature on the use of animal models for cystometry testing in the assessment of SCI-related NLUTD. We also discuss the advantages and disadvantages of various animal models, and opportunities for future research.
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Affiliation(s)
- Adam W. Doelman
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (A.W.D.); (F.S.)
| | - Femke Streijger
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (A.W.D.); (F.S.)
| | - Steve J. A. Majerus
- Department of Electrical, Computer and Systems Engineering, Case Western Reserve University, Cleveland, OH 44106, USA;
- Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA;
| | - Margot S. Damaser
- Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA;
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Brian K. Kwon
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (A.W.D.); (F.S.)
- Department of Orthopaedics, Vancouver Spine Surgery Institute, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
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Shimizu N, Saito T, Wada N, Hashimoto M, Shimizu T, Kwon J, Cho KJ, Saito M, Karnup S, de Groat WC, Yoshimura N. Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury. Int J Mol Sci 2023; 24:7885. [PMID: 37175592 PMCID: PMC10177842 DOI: 10.3390/ijms24097885] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/21/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder-urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.
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Affiliation(s)
- Nobutaka Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
- Pelvic Floor Center, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Tetsuichi Saito
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Mamoru Hashimoto
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Joonbeom Kwon
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Kang Jun Cho
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Sergei Karnup
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - William C. de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Hu JC, Osborn SL, Sanchez PC, Xu W, Christiansen BA, Kurzrock EA. Using uniaxial tensile testing to evaluate the biomechanical properties of bladder tissue after spinal cord injury in rat model. J Biomech 2023; 152:111571. [PMID: 37027962 DOI: 10.1016/j.jbiomech.2023.111571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 03/06/2023] [Accepted: 03/27/2023] [Indexed: 04/04/2023]
Abstract
To investigate the biomechanical properties of rat bladder tissue after spinal cord injury (SCI) using uniaxial tensile testing. Evidence suggests the bladder wall undergoes remodeling following SCI. There is limited data describing the biomechanical properties of bladder wall after SCI. This study describes the changes in elastic and viscoelastic mechanical properties of bladder tissue using a rat model after SCI. Seventeen adult rats received mid-thoracic SCI. Basso, Beattie, and Bresnahan (BBB) locomotor testing was performed on the rats 7-14 days after injury quantifying the degree of SCI. Bladder tissue samples were collected from controls and spinal injured rats at 2- and 9-weeks post-injury. Tissue samples underwent uniaxial stress relaxation to determine instantaneous and relaxation modulus as well as monotonic load-to failure to determine Young's modulus, yield stress and strain, and ultimate stress. SCI resulted in abnormal BBB locomotor scores. Nine weeks post-injury, instantaneous modulus decreased by 71.0% (p = 0.03) compared to controls. Yield strain showed no difference at 2 weeks post-injury but increased 78% (p = 0.003) in SCI rats at 9 weeks post-injury. Compared to controls, ultimate stress decreased 46.5% (p = 0.05) at 2 weeks post-injury in SCI rats but demonstrated no difference at 9 weeks post-injury. The biomechanical properties of rat bladder wall 2 weeks after SCI showed minimal difference compared to controls. By week 9, SCI bladders had a reduction in instantaneous modulus and increased yield strain. The findings indicate biomechanical differences can be identified between control and experimental groups at 2- and 9-week intervals using uniaxial testing.
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Ferreira A, Nascimento D, Cruz CD. Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin. Int J Mol Sci 2023; 24:ijms24043273. [PMID: 36834694 PMCID: PMC9959149 DOI: 10.3390/ijms24043273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 02/10/2023] Open
Abstract
Neurogenic detrusor overactivity (NDO) is a severe lower urinary tract disorder, characterized by urinary urgency, retention, and incontinence, as a result of a neurologic lesion that results in damage in neuronal pathways controlling micturition. The purpose of this review is to provide a comprehensive framework of the currently used animal models for the investigation of this disorder, focusing on the molecular mechanisms of NDO. An electronic search was performed with PubMed and Scopus for literature describing animal models of NDO used in the last 10 years. The search retrieved 648 articles, of which reviews and non-original articles were excluded. After careful selection, 51 studies were included for analysis. Spinal cord injury (SCI) was the most frequently used model to study NDO, followed by animal models of neurodegenerative disorders, meningomyelocele, and stroke. Rats were the most commonly used animal, particularly females. Most studies evaluated bladder function through urodynamic methods, with awake cystometry being particularly preferred. Several molecular mechanisms have been identified, including changes in inflammatory processes, regulation of cell survival, and neuronal receptors. In the NDO bladder, inflammatory markers, apoptosis-related factors, and ischemia- and fibrosis-related molecules were found to be upregulated. Purinergic, cholinergic, and adrenergic receptors were downregulated, as most neuronal markers. In neuronal tissue, neurotrophic factors, apoptosis-related factors, and ischemia-associated molecules are increased, as well as markers of microglial and astrocytes at lesion sites. Animal models of NDO have been crucial for understanding the pathophysiology of lower urinary tract (LUT) dysfunction. Despite the heterogeneity of animal models for NDO onset, most studies rely on traumatic SCI models rather than other NDO-driven pathologies, which may result in some issues when translating pre-clinical observations to clinical settings other than SCI.
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Affiliation(s)
- Ana Ferreira
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde-i3S and IBMC, Universidade do Porto, 4200-319 Porto, Portugal
| | - Diogo Nascimento
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal
| | - Célia Duarte Cruz
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde-i3S and IBMC, Universidade do Porto, 4200-319 Porto, Portugal
- Correspondence: ; Tel.: +351-220426740; Fax: +351-225513655
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Jhang JF, Jiang YH, Kuo HC. Current Understanding of the Pathophysiology and Novel Treatments of Interstitial Cystitis/Bladder Pain Syndrome. Biomedicines 2022; 10:biomedicines10102380. [PMID: 36289642 PMCID: PMC9598807 DOI: 10.3390/biomedicines10102380] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/08/2022] [Accepted: 09/17/2022] [Indexed: 12/19/2022] Open
Abstract
The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is multifactorial. Identifying the clinical characteristics and cystoscopic findings of bladder-centered IC/BPS facilitates optimal treatment strategies targeting the diseased urinary bladder. Patients with Hunner’s lesion (HIC) and without Hunner’s lesion (NHIC) should be treated differently. Based on the histopathological findings, NHIC can be treated with intravesical instillation of urothelial protective agents, such as hyaluronic acid, to cover the urothelial defects. In non-responders, chronic inflammation and higher urothelial dysfunction can be treated with intravesical botulinum toxin A injection, platelet-rich plasma injection, or low-energy shock wave treatment to reduce inflammation, increase tissue regeneration, and improve the urothelial barrier. Patients with HIC should be treated with electrocauterization first; augmentation enterocystoplasty should only be used in end-stage HIC when the contracted bladder is refractory to other treatments. The antiviral agent, valacyclovir, can be used in patients with HIC, small bladder capacity, and high-grade glomerulations. In addition, behavioral modification is always recommended from the beginning of treatment. Treatment with cognitive behavioral therapy interventions in combination with bladder therapy can reduce anxiety and improve treatment outcomes. Herein, recent advances in the pathophysiology and novel treatments for IC/BPS are reviewed.
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Affiliation(s)
| | | | - Hann-Chorng Kuo
- Correspondence: ; Tel.: +886-3-8561825 (ext. 2117); Fax: +886-3-8560794
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Development of Neurogenic Detrusor Overactivity after Thoracic Spinal Cord Injury Is Accompanied by Time-Dependent Changes in Lumbosacral Expression of Axonal Growth Regulators. Int J Mol Sci 2022; 23:ijms23158667. [PMID: 35955811 PMCID: PMC9368817 DOI: 10.3390/ijms23158667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 12/04/2022] Open
Abstract
Thoracic spinal cord injury (SCI) results in urinary dysfunction, which majorly affects the quality of life of SCI patients. Abnormal sprouting of lumbosacral bladder afferents plays a crucial role in this condition. Underlying mechanisms may include changes in expression of regulators of axonal growth, including chondroitin sulphate proteoglycans (CSPGs), myelin-associated inhibitors (MAIs) and repulsive guidance molecules, known to be upregulated at the injury site post SCI. Here, we confirmed lumbosacral upregulation of the growth-associated protein GAP43 in SCI animals with bladder dysfunction, indicating the occurrence of axonal sprouting. Neurocan and Phosphacan (CSPGs), as well as Nogo-A (MAI), at the same spinal segments were upregulated 7 days post injury (dpi) but returned to baseline values 28 dpi. In turn, qPCR analysis of the mRNA levels for receptors of those repulsive molecules in dorsal root ganglia (DRG) neurons showed a time-dependent decrease in receptor expression. In vitro assays with DRG neurons from SCI rats demonstrated that exposure to high levels of NGF downregulated the expression of some, but not all, receptors for those regulators of axonal growth. The present results, therefore, show significant molecular changes at the lumbosacral cord and DRGs after thoracic lesion, likely critically involved in neuroplastic events leading to urinary impairment.
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Ni J, Suzuki T, Karnup SV, Gu B, Yoshimura N. Nerve growth factor-mediated Na+ channel plasticity of bladder afferent neurons in mice with spinal cord injury. Life Sci 2022; 298:120524. [DOI: 10.1016/j.lfs.2022.120524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/20/2022] [Accepted: 03/28/2022] [Indexed: 11/28/2022]
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Tuttle TG, Lujan HL, Tykocki NR, DiCarlo SE, Roccabianca S. Remodeling of extracellular matrix in the urinary bladder of paraplegic rats results in increased compliance and delayed fiber recruitment 16 weeks after spinal cord injury. Acta Biomater 2022; 141:280-289. [PMID: 35032719 PMCID: PMC8898290 DOI: 10.1016/j.actbio.2022.01.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/17/2021] [Accepted: 01/07/2022] [Indexed: 01/21/2023]
Abstract
The ability of the urinary bladder to maintain low intravesical pressures while storing urine is key in ensuring proper organ function and highlights the key role that tissue mechanics plays in the lower urinary tract. Loss of supraspinal neuronal connections to the bladder after spinal cord injury can lead to remodeling of the structure of the bladder wall, which may alter its mechanical characteristics. In this study, we investigate if the morphology and mechanical properties of the bladder extracellular matrix are altered in rats 16 weeks after spinal cord injury as compared to animals who underwent sham surgery. We measured and quantified the changes in bladder geometry and mechanical behavior using histological analysis, tensile testing, and constitutive modeling. Our results suggest bladder compliance is increased in paraplegic animals 16 weeks post-injury. Furthermore, constitutive modeling showed that increased distensibility was driven by an increase in collagen fiber waviness, which altered the distribution of fiber recruitment during loading. STATEMENT OF SIGNIFICANCE: The ability of the urinary bladder to store urine under low pressure is key in ensuring proper organ function. This highlights the important role that mechanics plays in the lower urinary tract. Loss of control of neurologic connection to the bladder from spinal cord injury can lead to changes of the structure of the bladder wall, resulting in altered mechanical characteristics. We found that the bladder wall's microstructure in rats 16 weeks after spinal cord injury is more compliant than in healthy animals. This is significant since it is the longest time post-injury analyzed, to date. Understanding the extreme remodeling capabilities of the bladder in pathological conditions is key to inform new possible therapies.
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Affiliation(s)
- Tyler G Tuttle
- Michigan State University, Department of Mechanical Engineering, 428 S. Shaw Lane, Rm 2555, East Lansing, MI 48824, United States
| | - Heidi L Lujan
- Michigan State University, Department of Physiology, 567 Wilson Rd., Rm 2201, East Lansing, MI 48824, United States
| | - Nathan R Tykocki
- Michigan State University, Department of Pharmacology and Toxicology, 1355 Bogue St., B436 Life Science Building, East Lansing, MI 48824, United States
| | - Stephen E DiCarlo
- Michigan State University, Department of Physiology, 567 Wilson Rd., Rm 2201, East Lansing, MI 48824, United States
| | - Sara Roccabianca
- Michigan State University, Department of Mechanical Engineering, 428 S. Shaw Lane, Rm 2555, East Lansing, MI 48824, United States.
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Ikeda Y, Zabbarova I, Tyagi P, Hitchens TK, Wolf-Johnston A, Wipf P, Kanai A. Targeting neurotrophin and nitric oxide signaling to treat spinal cord injury and associated neurogenic bladder overactivity. CONTINENCE (AMSTERDAM, NETHERLANDS) 2022; 1:100014. [PMID: 37207253 PMCID: PMC10194419 DOI: 10.1016/j.cont.2022.100014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Purpose or the research Nearly 300,000 people are affected by spinal cord injury (SCI) with approximately 18,000 new cases annually, according to the National SCI Statistics Center. SCI affects physical mobility and impairs the function of multiple internal organs to cause lower urinary tract (LUT) dysfunctions manifesting as detrusor sphincter dyssynergia (DSD) and neurogenic detrusor overactivity (NDO) with detrimental consequences to the quality of life and increased morbidity. Multiple lines of evidence now support time dependent evolution of the complex SCI pathology which requires a multipronged treatment approach of immediate, specialized care after spinal cord trauma bookended by physical rehabilitation to improve the clinical outcomes. Instead of one size fits all treatment approach, we propose adaptive drug treatment to counter the time dependent evolution of SCI pathology, with three small molecule drugs with distinctive sites of action for the recovery of multiple functions. Principal results Our findings demonstrate the improvement in the recovery of hindlimb mobility and bladder function of spinal cord contused mice following administration of small molecules targeting neurotrophin receptors, LM11A-31 and LM22B-10. While LM11A-31 reduced the cell death in the spinal cord, LM22B-10 promoted cell survival and axonal growth. Moreover, the soluble guanylate cyclase (sGC) activator, cinaciguat, enhanced the revascularization of the SCI injury site to promote vessel formation, dilation, and increased perfusion. Major conclusions Our adaptive three drug cocktail targets different stages of SCI and LUTD pathology: neuroprotective effect of LM11A-31 retards the cell death that occurs in the early stages of SCI; and LM22B-10 and cinaciguat promote neural remodeling and reperfusion at later stages to repair spinal cord scarring, DSD and NDO. LM11A-31 and cinaciguat have passed phase I and IIa clinical trials and possess significant potential for accelerated clinical testing in SCI/LUTD patients.
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Affiliation(s)
- Youko Ikeda
- University of Pittsburgh, School of Medicine, Department of Medicine, Renal-Electrolyte Division, USA
- University of Pittsburgh, School of Medicine, Department of Pharmacology & Chemical Biology, USA
| | - Irina Zabbarova
- University of Pittsburgh, School of Medicine, Department of Medicine, Renal-Electrolyte Division, USA
| | - Pradeep Tyagi
- University of Pittsburgh, School of Medicine, Department of Urology, USA
| | - T. Kevin Hitchens
- University of Pittsburgh, School of Medicine, Animal Imaging Center, USA
| | - Amanda Wolf-Johnston
- University of Pittsburgh, School of Medicine, Department of Medicine, Renal-Electrolyte Division, USA
| | - Peter Wipf
- University of Pittsburgh, Dietrich School of Arts and Sciences, Department of Chemistry, USA
| | - Anthony Kanai
- University of Pittsburgh, School of Medicine, Department of Medicine, Renal-Electrolyte Division, USA
- University of Pittsburgh, School of Medicine, Department of Pharmacology & Chemical Biology, USA
- Correspondence to: University of Pittsburgh, School of Medicine, Department of Medicine, A1224 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. (A. Kanai)
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Wada N, Karnup S, Kadekawa K, Shimizu N, Kwon J, Shimizu T, Gotoh D, Kakizaki H, de Groat W, Yoshimura N. Current knowledge and novel frontiers in lower urinary tract dysfunction after spinal cord injury: Basic research perspectives. UROLOGICAL SCIENCE 2022; 33:101-113. [PMID: 36177249 PMCID: PMC9518811 DOI: 10.4103/uros.uros_31_22] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
This review article aims to summarize the recent advancement in basic research on lower urinary tract dysfunction (LUTD) following spinal cord injury (SCI) above the sacral level. We particularly focused on the neurophysiologic mechanisms controlling the lower urinary tract (LUT) function and the SCI-induced changes in micturition control in animal models of SCI. The LUT has two main functions, the storage and voiding of urine, that are regulated by a complex neural control system. This neural system coordinates the activity of two functional units in the LUT: the urinary bladder and an outlet including bladder neck, urethra, and striated muscles of the pelvic floor. During the storage phase, the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure and continence, and during the voiding phase, the outlet relaxes and the bladder contracts to promote efficient release of urine. SCI impairs voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following SCI, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However, the bladder does not empty efficiently because coordination between the bladder and urethral sphincter is lost. In animal models of SCI, hyperexcitability of silent C-fiber bladder afferents is a major pathophysiological basis of neurogenic LUTD, especially detrusor overactivity. Reflex plasticity is associated with changes in the properties of neuropeptides, neurotrophic factors, or chemical receptors of afferent neurons. Not only C-fiber but also Aδ-fiber could be involved in the emergence of neurogenic LUTD such as detrusor sphincter dyssynergia following SCI. Animal research using disease models helps us to detect the different contributing factors for LUTD due to SCI and to find potential targets for new treatments.
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12
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Begenisic T, Pavese C, Aiachini B, Nardone A, Rossi D. Dynamics of biomarkers across the stages of traumatic spinal cord injury - implications for neural plasticity and repair. Restor Neurol Neurosci 2021; 39:339-366. [PMID: 34657853 DOI: 10.3233/rnn-211169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Traumatic spinal cord injury (SCI) is a complex medical condition causing significant physical disability and psychological distress. While the adult spinal cord is characterized by poor regenerative potential, some recovery of neurological function is still possible through activation of neural plasticity mechanisms. We still have limited knowledge about the activation of these mechanisms in the different stages after human SCI. OBJECTIVE In this review, we discuss the potential role of biomarkers of SCI as indicators of the plasticity mechanisms at work during the different phases of SCI. METHODS An extensive review of literature related to SCI pathophysiology, neural plasticity and humoral biomarkers was conducted by consulting the PubMed database. Research and review articles from SCI animal models and SCI clinical trials published in English until January 2021 were reviewed. The selection of candidates for humoral biomarkers of plasticity after SCI was based on the following criteria: 1) strong evidence supporting involvement in neural plasticity (mandatory); 2) evidence supporting altered expression after SCI (optional). RESULTS Based on selected findings, we identified two main groups of potential humoral biomarkers of neural plasticity after SCI: 1) neurotrophic factors including: Brain derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrofin-3 (NT-3), and Insulin-like growth factor 1 (IGF-1); 2) other factors including: Tumor necrosis factor-alpha (TNF-α), Matrix Metalloproteinases (MMPs), and MicroRNAs (miRNAs). Plasticity changes associated with these biomarkers often can be both adaptive (promoting functional improvement) and maladaptive. This dual role seems to be influenced by their concentrations and time-window during SCI. CONCLUSIONS Further studies of dynamics of biomarkers across the stages of SCI are necessary to elucidate the way in which they reflect the remodeling of neural pathways. A better knowledge about the mechanisms underlying plasticity could guide the selection of more appropriate therapeutic strategies to enhance positive spinal network reorganization.
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Affiliation(s)
- Tatjana Begenisic
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Chiara Pavese
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Beatrice Aiachini
- Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Antonio Nardone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Daniela Rossi
- Laboratory for Research on Neurodegenerative Disorders, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
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13
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Philippova ES, Bazhenov IV, Ziryanov AV, Bazarny VV. Impact of intradetrusor botulinum toxin A injections on serum and urinary concentrations of nerve growth factor and brain-derived neurotrophic factor in patients with multiple sclerosis and neurogenic detrusor overactivity. Neurourol Urodyn 2020; 40:95-101. [PMID: 33034916 DOI: 10.1002/nau.24534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/18/2020] [Accepted: 09/30/2020] [Indexed: 11/07/2022]
Abstract
AIMS To evaluate the practical relevance of changes in serum and urinary neurotrophins levels in patients with multiple sclerosis (MS) and neurogenic lower urinary tract dysfunction (NLUTD) after intradetrusor injections of botulinum toxin A (BoNTA). METHODS The study included 36 patients with MS and NLUTD and 20 controls. The patients with NLUTD received intradetrusor injection of BoNTA (200 U). The nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels were measured in serum and urine at baseline and then at 1, 3, and 6 months by enzyme-linked immunosorbent assay. Urinary NGF and BDNF were normalized to creatinine (NGF/Cr, BDNF/Cr). Patients' assessment included urodynamic examination and Neurogenic Bladder Symptom Score (NBSS). RESULTS After BoNTA injections, no significant changes were observed in the serum NGF and BDNF or the urinary BDNF/Cr. The urinary NGF/Cr was significantly higher in MS patients (1.23 ± 0.34) at baseline compared with controls (0.084 ± 0.02; p = .021). The urinary NGF/Cr decreased to 0.51 ± 0.12 (p = .001) and 0.53 ± 0.32 (p = .005) at 1 and 3 months, increasing to 1.12 ± 0.49 (p = .003) at 6 months. The urinary NGF/Cr level at baseline demonstrated a low diagnostic accuracy in predicting a better response to the BoNTA treatment (area under the curve = 0.661; p = .047) and no correlation with the urodynamic parameters. CONCLUSIONS The urinary NGF/Cr at baseline or its reduction at the first month following treatment does not serve as a predictor for the response to the BoNTA injections or for urodynamic changes.
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Affiliation(s)
- Ekaterina S Philippova
- Department of Urology, Ural State Medical University, Ekaterinburg, Russia.,Regional Urological Center, Sverdlovsk Regional Clinical Hospital No. 1, Ekaterinburg, Russia
| | - Igor V Bazhenov
- Department of Urology, Ural State Medical University, Ekaterinburg, Russia.,Regional Urological Center, Sverdlovsk Regional Clinical Hospital No. 1, Ekaterinburg, Russia
| | - Alexander V Ziryanov
- Department of Urology, Ural State Medical University, Ekaterinburg, Russia.,Regional Urological Center, Sverdlovsk Regional Clinical Hospital No. 1, Ekaterinburg, Russia
| | - Vladimir V Bazarny
- Department of Clinical Laboratory Diagnosis and Bacteriology, Ural State Medical University, Ekaterinburg, Russia
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14
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Wada N, Yoshimura N, Kurobe M, Saito T, Tyagi P, Kakizaki H. The early, long‐term inhibition of brain‐derived neurotrophic factor improves voiding, and storage dysfunctions in mice with spinal cord injury. Neurourol Urodyn 2020; 39:1345-1354. [DOI: 10.1002/nau.24385] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/23/2020] [Accepted: 04/30/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Naoki Wada
- Department of Renal and Urologic SurgeryAsahikawa Medical UniversityAsahikawa Japan
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburgh Pennsylvania
| | - Naoki Yoshimura
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburgh Pennsylvania
| | - Masahiro Kurobe
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburgh Pennsylvania
| | - Tetsuichi Saito
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburgh Pennsylvania
| | - Pradeep Tyagi
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburgh Pennsylvania
| | - Hidehiro Kakizaki
- Department of Renal and Urologic SurgeryAsahikawa Medical UniversityAsahikawa Japan
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15
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Therapeutic Effect of Botulinum Toxin A on Sensory Bladder Disorders-From Bench to Bedside. Toxins (Basel) 2020; 12:toxins12030166. [PMID: 32182780 PMCID: PMC7150911 DOI: 10.3390/toxins12030166] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 02/27/2020] [Accepted: 03/06/2020] [Indexed: 12/22/2022] Open
Abstract
Bladder oversensitivity arises from several different conditions involving the bladder, bladder outlet, systemic or central nervous system diseases. Increase of the bladder sensation results from activation of the sensory receptors in the urothelial cells or suburothelial tissues. Medical treatment targeting the overactive bladder (OAB) or interstitial cystitis (IC) might relieve oversensitive bladder symptoms (frequency, urgency and pain) in a portion of patients, but a certain percentage of patients still need active management. Botulinum toxin A (BoNT-A) has been demonstrated to have anti-inflammatory and antinociceptive effects in bladder sensory disorders and has been shown effective in the reduction of bladder oversensitivity and the increase of functional bladder capacity. For patients with OAB, urgency and urinary incontinence improved, while in patients with IC, bladder pain could be relieved in association with reduction of bladder oversensitivity after BoNT-A intravesical injection. Histological evidence has confirmed the therapeutic mechanism and clinical efficacy of intravesical BoNT-A injection on patients with OAB or IC. Bladder oversensitivity can also be relieved with the instillation of liposome encapsulated BoNT-A or low energy show waves (LESWs), which enable the BoNT-A molecule to penetrate into the urothelium and suburothelial space without affecting the detrusor contractility. Liposome encapsulated BoNT-A or combined LESWs and BoNT-A instillation might be future treatment alternatives for bladder oversensitivity in sensory bladder disorders.
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16
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Yeh TC, Chen PC, Su YR, Kuo HC. Effect of Botulinum Toxin A on Bladder Pain-Molecular Evidence and Animal Studies. Toxins (Basel) 2020; 12:toxins12020098. [PMID: 32028597 PMCID: PMC7076962 DOI: 10.3390/toxins12020098] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/31/2020] [Accepted: 01/31/2020] [Indexed: 12/15/2022] Open
Abstract
Botulinum toxin A (BTX-A) is a powerful neurotoxin with long-lasting activity that blocks muscle contractions. In addition to effects on neuromuscular junctions, BTX-A also plays a role in sensory feedback loops, suggesting the potentiality for pain relief. Although the only approved indications for BTX-A in the bladder are neurogenic detrusor overactivity and refractory overactive bladder, BTX-A injections to treat bladder pain refractory to conventional therapies are also recommended. The mechanism of BTX-A activity in bladder pain is complex, with several hypotheses proposed in recent studies. Here we comprehensively reviewed properties of BTX-A in peripheral afferent and efferent nerves, the inhibition of nociceptive neurotransmitter release, the reduction of stretch-related visceral pain, and its anti-inflammatory effects on the bladder urothelium. Studies have also revealed possible effects of BTX-A in the human brain. However, further basic and clinical studies are warranted to provide solid evidence-based support in using BTX-A to treat bladder pain.
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Affiliation(s)
- Ting-Chun Yeh
- Division of Urology, Department of Surgery, Taiwan Adventist Hospital, Taipei City 105, Taiwan;
| | - Po-Cheng Chen
- Department of Urology, En Chu Kong Hospital, New Taipei City 237, Taiwan;
| | - Yann-Rong Su
- Department of Urology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City 300, Taiwan;
| | - Hann-Chorng Kuo
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien City 970, Taiwan
- Correspondence:
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17
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Sangsiri S, Xu H, Fernandes R, Fink GD, Lujan HL, DiCarlo SE, Galligan JJ. Spinal cord injury alters purinergic neurotransmission to mesenteric arteries in rats. Am J Physiol Heart Circ Physiol 2019; 318:H223-H237. [PMID: 31774690 DOI: 10.1152/ajpheart.00525.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Complications associated with spinal cord injury (SCI) result from unregulated reflexes below the lesion level. Understanding neurotransmission distal to the SCI could improve quality of life by mitigating complications. The long-term impact of SCI on neurovascular transmission is poorly understood, but reduced sympathetic activity below the site of SCI enhances arterial neurotransmission (1). We studied sympathetic neurovascular transmission using a rat model of long-term paraplegia (T2-3) and tetraplegia (C6-7). Sixteen weeks after SCI, T2-3 and C6-7 rats had lower blood pressure (BP) than sham rats (103 ± 2 and 97 ± 4 vs. 117 ± 6 mmHg, P < 0.05). T2-3 rats had tachycardia (410 ± 6 beats/min), and C6-7 rats had bradycardia (299 ± 10 beats/min) compared with intact rats (321 ± 4 beats/min, P < 0.05). Purinergic excitatory junction potentials (EJPs) were measured in mesenteric arteries (MA) using microlectrodes, and norepinephrine (NE) release was measured using amperometry. NE release was similar in all groups, while EJP frequency-response curves from T2-3 and C6-7 rats were left-shifted vs. sham rats. EJPs in T2-3 and C6-7 rats showed facilitation followed by run-down during stimulation trains (10 Hz, 50 stimuli). MA reactivity to exogenous NE and ATP was similar in all rats. In T2-3 and C6-7 rats, NE content was increased in left cardiac ventricles compared with intact rats, but was not changed in MA, kidney, or spleen. Our data indicate that peripheral purinergic, but not adrenergic, neurotransmission increases following SCI via enhanced ATP release from periarterial nerves. Sympathetic BP support is reduced after SCI, but improving neurotransmitter release might maintain cardiovascular stability in individuals living with SCI.NEW & NOTEWORTHY This study revealed increased purinergic, but not noradrenergic, neurotransmission to mesenteric arteries in rats with spinal cord injury (SCI). An increased releasable pool of ATP in periarterial sympathetic nerves may contribute to autonomic dysreflexia following SCI, suggesting that purinergic neurotransmission may be a therapeutic target for maintaining stable blood pressure in individuals living with SCI. The selective increase in ATP release suggests that ATP and norepinephrine may be stored in separate synaptic vesicles in periarterial sympathetic varicosities.
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Affiliation(s)
- Sutheera Sangsiri
- Department of Preclinical Science, Thammasat University, Pathumthani, Thailand.,Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
| | - Hui Xu
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.,Neuroscience Program, Michigan State University, East Lansing, Michigan
| | - Roxanne Fernandes
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
| | - Greg D Fink
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.,Neuroscience Program, Michigan State University, East Lansing, Michigan
| | - Heidi L Lujan
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Stephen E DiCarlo
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - James J Galligan
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.,Neuroscience Program, Michigan State University, East Lansing, Michigan
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18
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Shimizu N, Wada N, Shimizu T, Suzuki T, Kurobe M, Kanai AJ, de Groat WC, Hashimoto M, Hirayama A, Uemura H, Yoshimura N. Role of p38 MAP kinase signaling pathways in storage and voiding dysfunction in mice with spinal cord injury. Neurourol Urodyn 2019; 39:108-115. [PMID: 31579964 DOI: 10.1002/nau.24170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 09/07/2019] [Indexed: 11/09/2022]
Abstract
AIM To investigate the role of p38 MAP kinase in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS Cystometry and external urethral sphincter-electromyography were performed under an awake condition in 4-week SCI female mice. Two weeks after SCI, a catheter connected to an osmotic pump filled with a p38 mitogen-activated protein kinase (MAPK) inhibitor or artificial cerebrospinal fluid (CSF) was implanted into the intrathecal space of L6-S1 spinal cord for continuous intrathecal instillation at infusion rate of 0.51 μL/h for 2 weeks before the urodynamic study. L6 dorsal root ganglia were then removed from CSF and p38 MAPK inhibitor-treated SCI mice as well as from CSF-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) transcripts by real-time polymerase chain reaction. RESULTS In p38 MAPK inhibitor-treated SCI mice, nonvoiding contractions during bladder filling, bladder capacity, and post-void residual volume were significantly reduced while micturition pressure and voiding efficiency were significantly increased in comparison to these measurements in CSF-treated SCI mice. The expression of TRPV1, TNF-α, and iNOS messenger RNA was increased in SCI mice compared with expression in spinal intact mice and significantly decreased after p38 MAPK inhibitor treatment. CONCLUSIONS The p38 MAPK signaling pathway in bladder sensory neurons or in the spinal cord plays an important role in storage and voiding problems such as detrusor overactivity and inefficient voiding after SCI.
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Affiliation(s)
- Nobutaka Shimizu
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Urology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Naoki Wada
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Takahisa Suzuki
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Masahiro Kurobe
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mamoru Hashimoto
- Department of Urology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Akihide Hirayama
- Department of Urology, Faculty of Medicine, Kindai University Nara Hospital, Nara, Japan
| | - Hirotsugu Uemura
- Department of Urology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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19
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Wada N, Shimizu T, Shimizu N, Kurobe M, de Groat WC, Tyagi P, Kakizaki H, Yoshimura N. Therapeutic effects of inhibition of brain-derived neurotrophic factor on voiding dysfunction in mice with spinal cord injury. Am J Physiol Renal Physiol 2019; 317:F1305-F1310. [PMID: 31566429 DOI: 10.1152/ajprenal.00239.2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
We investigated the involvement of brain-derived neurotrophic factor (BDNF) in bladder and urethral dysfunction using spinal cord-injured mice. We evaluated bladder and urethral function of female mice with 4-wk spinal cord injury (SCI) by filling cystometry and electromyography (EMG) of the external urethral sphincter (EUS) under a conscious condition. Anti-BDNF antibodies (10 μg·kg-1·h-1) were administered in some mice for 1 wk before the evaluation. Bladder and spinal (L6-S1) BDNF protein levels were examined by ELISA. Transcript levels of transient receptor potential channels or acid-sensing ion channels (Asic) in L6-S1 dorsal root ganglia were evaluated by RT-PCR. Voided volume and voiding efficiency were significantly increased without any changes in nonvoiding contractions, and the duration of reduced EMG activity during the voiding phase was significantly prolonged in anti-BDNF antibody-treated SCI mice. Compared with spinal cord-intact mice, SCI mice showed increased concentrations of bladder and spinal BDNF. Anti-BDNF antibody treatment decreased bladder and spinal BDNF protein concentrations of SCI mice. Asic2 and Asic3 transcripts were significantly increased after SCI but decreased after anti-BDNF antibody administration. These results indicate that upregulated expression of bladder and spinal BDNF is involved in the emergence of inefficient voiding in SCI mice. Thus, BDNF-targeting treatment could be an effective modality for the treatment of voiding problems, including inefficient voiding and detrusor sphincter dyssynergia after SCI.
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Affiliation(s)
- Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nobutaka Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Masahiro Kurobe
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hidehiro Kakizaki
- Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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20
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Karamali M, Shafabakhsh R, Ghanbari Z, Eftekhar T, Asemi Z. Molecular pathogenesis of interstitial cystitis/bladder pain syndrome based on gene expression. J Cell Physiol 2019; 234:12301-12308. [PMID: 30609029 DOI: 10.1002/jcp.28009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022]
Abstract
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder inflammation that leads to chronic bladder pain and urinary urgency and frequency. The presentation of IC/PBS is heterogeneous, and it is classified as ulcerative IC/PBS and nonulcerative IC/PBS. The main cause of IC/PBS is thought to be a persistent inflammatory condition in the bladder, though the actual pathophysiology has not been identified yet. Although the underlying pathophysiology of IC/PBS is not completely understood, several theories for the etiology of this syndrome have been suggested, including deficiency of the glycosaminoglycan covering urothelium surface that results in leaky urothelium infection, immunological etiology, activated mast cells, neural changes, and inflammation. In addition, there are no gold standards for the detection of this disorder to date. So, determination of gene expression and its role in different signaling pathways in the pathogenesis of this heterogeneous disorder contribute to the more efficient cognition of the pathophysiology of this disease and to the design of effective treatments and molecular diagnostic methods for IC/PBS.
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Affiliation(s)
- Maryam Karamali
- Reproductive Health Research Center, Tehran University of Medical Science, Tehran, Iran.,Department of Gynecology & Obstetrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Zinat Ghanbari
- Reproductive Health Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Tahereh Eftekhar
- Reproductive Health Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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21
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Coelho A, Oliveira R, Antunes-Lopes T, Cruz CD. Partners in Crime: NGF and BDNF in Visceral Dysfunction. Curr Neuropharmacol 2019; 17:1021-1038. [PMID: 31204623 PMCID: PMC7052822 DOI: 10.2174/1570159x17666190617095844] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/23/2019] [Accepted: 06/03/2019] [Indexed: 12/12/2022] Open
Abstract
Neurotrophins (NTs), particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), have attracted increasing attention in the context of visceral function for some years. Here, we examined the current literature and presented a thorough review of the subject. After initial studies linking of NGF to cystitis, it is now well-established that this neurotrophin (NT) is a key modulator of bladder pathologies, including Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS. NGF is upregulated in bladder tissue and its blockade results in major improvements on urodynamic parameters and pain. Further studies expanded showed that NGF is also an intervenient in other visceral dysfunctions such as endometriosis and Irritable Bowel Syndrome (IBS). More recently, BDNF was also shown to play an important role in the same visceral dysfunctions, suggesting that both NTs are determinant factors in visceral pathophysiological mechanisms. Manipulation of NGF and BDNF improves visceral function and reduce pain, suggesting that clinical modulation of these NTs may be important; however, much is still to be investigated before this step is taken. Another active area of research is centered on urinary NGF and BDNF. Several studies show that both NTs can be found in the urine of patients with visceral dysfunction in much higher concentration than in healthy individuals, suggesting that they could be used as potential biomarkers. However, there are still technical difficulties to be overcome, including the lack of a large multicentre placebo-controlled studies to prove the relevance of urinary NTs as clinical biomarkers.
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Affiliation(s)
| | | | | | - Célia Duarte Cruz
- Address correspondence to this author at the Department of Experimental Biology, Experimental Biology Unit, Faculty of Medicine of the University of Porto, Alameda Hernâni Monteiro; Tel: 351 220426740; Fax: +351 225513655; E-mail:
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22
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Dellis AE, Papatsoris AG. Bridging pharmacotherapy and minimally invasive surgery in interstitial cystitis/bladder pain syndrome treatment. Expert Opin Pharmacother 2018; 19:1369-1373. [PMID: 30074829 DOI: 10.1080/14656566.2018.1505865] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful and debilitating clinical entity which is challenging to diagnose and even more difficult to treat. Unfortunately, none of the existing oral and intravesical medications have been established as effective and therefore relevant research is ongoing. Areas covered: In this review, the authors present established and emerging treatment options for IC/BPS in terms of medication and minimal invasive procedures. Both American and European Urological Association Guidelines recommend multimodal behavioral techniques alongside oral (e.g. amitriptyline and pentosan polysulfate sodium) or minimally invasive treatments (e.g. dimethyl sulfoxide, botulinum toxin, chondroitin sulfate, triamcinolone, hyaluronic acid, and lidocaine). Novel treatment modalities include immunomodulating drugs, stem cell therapy, nerve growth factor, and ASP6294. Expert opinion: IC/BPS is still a pathophysiological enigma with multifactorial etiopathogenesis that may be controlled but not completely cured. Patient-tailored phenotype-directed multimodal therapy is the most promising treatment strategy. Combined phenotypic categorization with specific biomarkers could help toward better treatment.
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Affiliation(s)
- Athanasios E Dellis
- a 2nd Department of Surgery, Aretaieion Academic Hospital, School of Medicine , National and Kapodistrian University of Athens , Athens , Greece.,b 1st Department of Urology, Laikon General Hospital, School of Medicine , National and Kapodistrian University of Athens , Athens , Greece
| | - Athanasios G Papatsoris
- c 2nd Department of Urology, Sismanogleion General Hospital, School of Medicine , National and Kapodistrian University of Athens , Athens , Greece
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23
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Effects of nerve growth factor neutralization on TRP channel expression in laser-captured bladder afferent neurons in mice with spinal cord injury. Neurosci Lett 2018; 683:100-103. [PMID: 29960052 DOI: 10.1016/j.neulet.2018.06.049] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/18/2018] [Accepted: 06/26/2018] [Indexed: 12/13/2022]
Abstract
Nerve growth factor (NGF) is reportedly involved in the changes in C-fiber bladder afferent pathways that induce detrusor overactivity (DO) following spinal cord injury (SCI). This study examined the roles of NGF in TRP channel expression in bladder afferent neurons in mice with SCI using laser-capture microdissection (LCM) methods. Spinal intact (SI) and SCI mice were divided into 3 groups: (1) SI with vehicle treatment; (2) SCI with vehicle treatment; and (3) SCI with anti-NGF antibody. Two weeks after SCI, an osmotic pump was placed subcutaneously into the back of the mice and vehicle or anti-NGF antibody was administered at a rate of 10 μg/kg per hour for two weeks. Four weeks after SCI, the L6 dorsal root ganglia (DRG) were removed. Expression of the TRPV1, TRPC1, TRPC3, and TRPC6 genes was analyzed using real-time polymerase chain reaction (PCR) following LCM of the bladder afferent neurons, which were labeled by Fast Blue injected into the bladder wall 1 week prior to tissue removal. The mRNA expression of TRPV1 was found to be higher in vehicle-treated SCI mice than in SI mice. The expression level of TRPC3 and TRPC6 in vehicle-treated SCI mice was lower than in SI mice. However, in SCI mice treated with anti-NGF antibody, the mRNA expression of TRPV1 was lower, and the mRNA levels of TRPC3 and TRPC6 were higher than in vehicle-SCI mice. These results suggest that the NGF-dependent changes in specific TRP channel genes, such as TRPV1, TRPC3, and TRPC6, could be involved in SCI-induced afferent hyperexcitability and DO.
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24
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Epidemiology and pathophysiology of neurogenic bladder after spinal cord injury. World J Urol 2018; 36:1517-1527. [DOI: 10.1007/s00345-018-2301-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 04/19/2018] [Indexed: 10/16/2022] Open
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25
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Shimizu T, Majima T, Suzuki T, Shimizu N, Wada N, Kadekawa K, Takai S, Takaoka E, Kwon J, Kanai AJ, de Groat WC, Tyagi P, Saito M, Yoshimura N. Nerve growth factor-dependent hyperexcitability of capsaicin-sensitive bladder afferent neurones in mice with spinal cord injury. Exp Physiol 2018; 103:896-904. [PMID: 29603450 DOI: 10.1113/ep086951] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 03/20/2018] [Indexed: 01/03/2023]
Abstract
NEW FINDINGS What is the central question of this study? Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent pathways after spinal cord injury (SCI)? What is the main finding and its importance? Neutralization of NGF by anti-NGF antibody treatment reversed the SCI-induced increase in the number of action potentials and the reduction in spike thresholds and A-type K+ current density in mouse capsaicin-sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent neurones attributable to the reduction in A-type K+ channel activity in SCI. ABSTRACT Nerve growth factor (NGF) has been implicated as an important mediator in the induction of C-fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti-NGF antibody (NGF-Ab) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF-Ab (10 μg kg-1 h-1 , s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast-Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurones were prepared. Whole-cell patch-clamp recordings were then performed in FB-labelled neurones. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI-induced changes were reversed by NGF-Ab. Densities of slow-decaying A-type K+ (KA ) and sustained delayed rectifier-type K+ currents were significantly reduced by SCI. The NGF-Ab treatment reversed the SCI-induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin-sensitive C-fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI.
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Affiliation(s)
- Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan.,Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Tsuyoshi Majima
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Takahisa Suzuki
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Nobutaka Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Katsumi Kadekawa
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Shun Takai
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Eiichiro Takaoka
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Joonbeom Kwon
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - William C de Groat
- Department of Pharmacology & Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.,Department of Pharmacology & Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
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26
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Ogawa T, Ishizuka O, Ueda T, Tyagi P, Chancellor MB, Yoshimura N. Pharmacological management of interstitial cystitis /bladder pain syndrome and the role cyclosporine and other immunomodulating drugs play. Expert Rev Clin Pharmacol 2018; 11:495-505. [PMID: 29575959 DOI: 10.1080/17512433.2018.1457435] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Interstitial cystitis/bladder pain syndrome (IC/BPS) is a symptomatic disorder characterized by pelvic pain and urinary frequency. Immunological responses are considered as one of the possible etiologies of IC/BPS. In this review, we focused on emerging targets, especially on those modulating immunological mechanisms for the treatments of IC/BPS. Area covered: This review was based on the literature search of PubMed/MEDLINE, for which key words following bladder pain syndrome, interstitial cystitis, and/or cyclosporine A (CyA) were used. We discussed current treatments and the drugs targeting the immune responses including CyA and other drugs with different mechanisms including NGF antibodies and P2X3 antagonists. Expert commentary: IC/BPS is often difficult to treat by current treatments. Immunosuppression agents, especially CyA are considered as effective treatments for IC/BPS with Hunner's lesion because these drugs suppress the inflammatory responses in the bladder underlying urinary symptoms of the disease. Base on the previous literatures, we should use CyA for the refractory IC/BPS, especially that with Hunner's lesion due to its side effects. New drugs targeting other mechanisms such as urothelial or afferent nerve dysfunction or new delivery systems such as sustained drug releasing devices or gene therapy techniques may be promising for the future treatments of IC/BPS.
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Affiliation(s)
- Teruyuki Ogawa
- a Department of Urology , Shinshu University School of Medicine , Matsumoto , Japan.,b Department of Urology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA
| | - Osamu Ishizuka
- a Department of Urology , Shinshu University School of Medicine , Matsumoto , Japan
| | - Tomohiro Ueda
- c Department of Urology , Ueda Clinic , Kyoto , Japan
| | - Pradeep Tyagi
- b Department of Urology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA
| | - Michael B Chancellor
- d Department of Urology , Oakland University William Beaumont School of Medicine , Royal Oak , MI , USA
| | - Naoki Yoshimura
- b Department of Urology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.,c Department of Urology , Ueda Clinic , Kyoto , Japan
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27
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Ryu JC, Tooke K, Malley SE, Soulas A, Weiss T, Ganesh N, Saidi N, Daugherty S, Saragovi U, Ikeda Y, Zabbarova I, Kanai AJ, Yoshiyama M, Farhadi HF, de Groat WC, Vizzard MA, Yoon SO. Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 2018; 128:1772-1786. [PMID: 29584618 DOI: 10.1172/jci97837] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 02/08/2018] [Indexed: 12/15/2022] Open
Abstract
Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro-nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase-positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.
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Affiliation(s)
- Jae Cheon Ryu
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Katharine Tooke
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Susan E Malley
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Anastasia Soulas
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Tirzah Weiss
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Nisha Ganesh
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Nabila Saidi
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Stephanie Daugherty
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Uri Saragovi
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Youko Ikeda
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Irina Zabbarova
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mitsuharu Yoshiyama
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Japan
| | - H Francis Farhadi
- Department of Neurological Surgery, Ohio State University, Columbus, Ohio, USA
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Margaret A Vizzard
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Sung Ok Yoon
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
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Wada N, Shimizu T, Shimizu N, de Groat WC, Kanai AJ, Tyagi P, Kakizaki H, Yoshimura N. The effect of neutralization of nerve growth factor (NGF) on bladder and urethral dysfunction in mice with spinal cord injury. Neurourol Urodyn 2018. [PMID: 29516546 DOI: 10.1002/nau.23539] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIMS To investigate the role of nerve growth factor (NGF) in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS Using 4-week SCI mice, single-filling cystometry and external urethral sphincter (EUS)-electromyography were performed under an awake condition. In some SCI mice, anti-NGF antibodies (10 µg/kg/h) were administered for 1 or 2 weeks before the urodynamic study. NGF levels in the bladder and L6/S1 spinal cord were assayed by ELISA. The transcript levels of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured by RT-PCR. RESULTS In SCI mice, the area under the curve of non-voiding contractions (NVCs) during the storage phase was significantly decreased in both 1- and 2-week anti-NGF antibody-treated SCI groups. However, EUS-electromyogram parameters during voiding were not altered by the treatment. Bladder mucosal and spinal NGF levels were decreased after 2 weeks of anti-NGF antibody treatment. TRPA1 and TRPV1 transcripts in L6/S1 DRG were significantly decreased after 1- or 2-week anti-NGF treatment. CONCLUSIONS In SCI mice, NGF is involved in the emergence of NVCs in association with increased expression of TRP receptors that are predominantly found in C-fiber afferent pathways. Thus, NGF targeting treatments could be effective for treating storage problems such as detrusor overactivity after SCI.
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Affiliation(s)
- Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nobutaka Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hidehiro Kakizaki
- Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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29
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Lujan HL, Tonson A, Wiseman RW, DiCarlo SE. Chronic, complete cervical 6-7 cord transection: distinct autonomic and cardiac deficits. J Appl Physiol (1985) 2018; 124:1471-1482. [PMID: 29470149 DOI: 10.1152/japplphysiol.01104.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Spinal cord injury (SCI) resulting in tetraplegia is a devastating, life-changing insult causing paralysis and sensory impairment as well as distinct autonomic dysfunction that triggers compromised cardiovascular, bowel, bladder, and sexual activity. Life becomes a battle for independence as even routine bodily functions and the smallest activity of daily living become major challenges. Accordingly, there is a critical need for a chronic preclinical model of tetraplegia. This report addresses this critical need by comparing, for the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses each week for 4 wk in 12 sham-operated intact rats and 12 rats with chronic, complete C6-7 spinal cord transection. Loss of supraspinal control to all sympathetic preganglionic neurons projecting to the heart and vasculature resulted in a profound bradycardia and hypotension, reduced cardiac sympathetic and parasympathetic tonus, reduced reflex- and stress-induced sympathetic responses, and reduced sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination of the nucleus ambiguus and stellate ganglia supports the profound and distinct autonomic and cardiac deficits and reliance on angiotensin to maintain cardiovascular stability following chronic, complete cervical6-7 cord transection. NEW & NOTEWORTHY For the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses were studied in rats with chronic, complete C6-7 cord transection. Loss of supraspinal control of all sympathetic preganglionic neurons reduced cardiac sympathetic and parasympathetic tonus, reflex and stress-induced sympathetic responses, and sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination supports the distinct deficits associated with cervical cord injury.
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Affiliation(s)
- Heidi L Lujan
- Department of Physiology, Michigan State University College of Osteopathic Medicine , East Lansing, Michigan
| | - Anne Tonson
- Department of Physiology, Michigan State University College of Osteopathic Medicine , East Lansing, Michigan
| | - Robert W Wiseman
- Department of Physiology, Michigan State University College of Osteopathic Medicine , East Lansing, Michigan
| | - Stephen E DiCarlo
- Department of Physiology, Michigan State University College of Osteopathic Medicine , East Lansing, Michigan
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30
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Kashyap MP, Pore SK, de Groat WC, Chermansky CJ, Yoshimura N, Tyagi P. BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity. Am J Physiol Renal Physiol 2017; 315:F45-F56. [PMID: 29092846 DOI: 10.1152/ajprenal.00386.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Elevated levels of brain-derived neurotrophic factor (BDNF) in urine of overactive bladder (OAB) patients support the association of BDNF with OAB symptoms, but the causality is not known. Here, we investigated the functionality of BDNF overexpression in rat bladder following bladder wall transfection of either BDNF or luciferase (luciferase) transgenes (10 µg). One week after transfection, BDNF overexpression in bladder tissue and elevation of urine BDNF levels were observed together with increased transcript of BDNF, its cognate receptors (TrkB and p75NTR), and downstream PLCγ isoforms in bladder. BDNF overexpression can induce the bladder overactivity (BO) phenotype which is demonstrated by the increased voiding pressure and reduced intercontractile interval during transurethral open cystometry under urethane anesthesia. A role for BDNF-mediated enhancement of prejunctional cholinergic transmission in BO is supported by the significant increase in the atropine- and neostigmine-sensitive component of nerve-evoked contractions and upregulation of choline acetyltransferase, vesicular acetylcholine transporter, and transporter Oct2 and -α1 receptors. In addition, higher expression of transient receptor channels (TRPV1 and TRPA1) and pannexin-1 channels in conjunction with elevation of ATP and neurotrophins in bladder and also in L6/S1 dorsal root ganglia together support a role for sensitized afferent nerve terminals in BO. Overall, genomic changes in efferent and afferent neurons of bladder induced by the overexpression of BDNF per se establish a mechanistic link between elevated BDNF levels in urine and dysfunctional voiding observed in animal models and in OAB patients.
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Affiliation(s)
- Mahendra P Kashyap
- Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Subrata K Pore
- Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | | | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
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31
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WenBo W, Fei Z, YiHeng D, Wei W, TingMang Y, WenHao Z, QianRu L, HaiTao L. Human Umbilical Cord Mesenchymal Stem Cells Overexpressing Nerve Growth Factor Ameliorate Diabetic Cystopathy in Rats. Neurochem Res 2017; 42:3537-3547. [PMID: 28952006 DOI: 10.1007/s11064-017-2401-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 08/10/2017] [Accepted: 09/11/2017] [Indexed: 12/18/2022]
Abstract
Diabetic cystopathy is a common complication of voiding disorders in diabetes mellitus. Neuropathy and bladder remodeling underlie the lack of efficacy of pharmacological and surgical treatments. Previous studies have shown that decreased levels of nerve growth factor (NGF) are closely associated with disease progression. Besides, application of human umbilical cord mesenchymal stem cells (hUC-MSCs) is also considered a promising therapeutic strategy for treatment of diabetic neuropathy. In our study, we determine the therapeutic efficacy and mechanisms of hUC-MSCs which transfected with NGF geen in ameliorating diabetic cystopathy for the first time. We transducted hUC-MSCs with NGF-expressing lentivirus so that the hUC-MSCs can express NGF efficiently, then the NGF-expressing hUC-MSCs were intrathecally administrated in L6-S1 spinal cord of diabetic rats 3 days after induced by streptozotocin. Nine weeks later, the level of neurotrophins and voiding function of bladder were detected. Results show that improvements in voiding function were related to the neurotrophins and cytokines released by the intrathecally transplanted hUC-MSCs. In addition, the hUC-MSCs also differentiated into neurons and astrocytes within the spinal cord in rats. These two mechanisms play a combined role in neural regeneration and the amelioration of the symptoms of diabetic cystopathy.
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Affiliation(s)
- Wu WenBo
- Department of Urology, Shanghai General Hospital (Shanghai Peoples Hosp 1), Shanghai JiaoTong University School of Medicine, 100 Haining Rd, Shanghai, 200080, China
| | - Zhang Fei
- Department of Urology, The Affiliated Hospital of School of Medicine of NingBo University, Ningbo, China
| | - Du YiHeng
- Department of Urology, Shanghai General Hospital (Shanghai Peoples Hosp 1), Shanghai JiaoTong University School of Medicine, 100 Haining Rd, Shanghai, 200080, China
| | - Wang Wei
- Department of Urology, Shanghai General Hospital (Shanghai Peoples Hosp 1), Shanghai JiaoTong University School of Medicine, 100 Haining Rd, Shanghai, 200080, China
| | - Yan TingMang
- Department of Urology, Shanghai General Hospital (Shanghai Peoples Hosp 1), Shanghai JiaoTong University School of Medicine, 100 Haining Rd, Shanghai, 200080, China
| | - Zhou WenHao
- Department of Urology, Shanghai General Hospital (Shanghai Peoples Hosp 1), Shanghai JiaoTong University School of Medicine, 100 Haining Rd, Shanghai, 200080, China
| | - Liu QianRu
- QUFU Normal University, Jining, Shandong, China
| | - Liu HaiTao
- Department of Urology, Shanghai General Hospital (Shanghai Peoples Hosp 1), Shanghai JiaoTong University School of Medicine, 100 Haining Rd, Shanghai, 200080, China.
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Treatment of obesity-associated overactive bladder by the phosphodiesterase type-4 inhibitor roflumilast. Int Urol Nephrol 2017; 49:1723-1730. [PMID: 28756610 DOI: 10.1007/s11255-017-1671-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 07/25/2017] [Indexed: 12/11/2022]
Abstract
PURPOSE To prove that phosphodiesterase type-4 inhibitors could potentially treat obesity-associated overactive bladder through modulation of the systemic inflammatory response. METHODS In this 12-week study, 90 female Sprague-Dawley rats were divided into three groups: (1) vehicle-treated normal diet (ND)-fed rats; (2) vehicle-treated high-fat diet (HFD)-fed rats; and (3) roflumilast-treated HFD-fed rats. Oral roflumilast (5 mg/kg/day) was administered during the last 4 weeks of HFD feeding in the test group. At 12 weeks, a urodynamic study was performed in ten rats of each group. Bladder tissue was extracted, the bladder mucosa was separated under microscopy, and bladder detrusor smooth muscle (DSM) expression of TNF-α, interleukin (IL)-6, IL-1β, and nuclear factor kappa B (NF-κB) were analyzed using Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS Bodyweights of the HFD-fed rats significantly increased and were not ameliorated by roflumilast treatment. Cystometry evidenced augmented frequency and non-void contractions in obese rats that were also prevented by roflumilast. These alterations were accompanied by a markedly increased expression of TNF-α, IL-6, IL-1β, and NF-κB in DSM of obese rats. Furthermore, roflumilast decreased expression of inflammatory factors in DSM. CONCLUSIONS Oral treatment with roflumilast in rats fed an HFD restores normal bladder function and downregulates expression of inflammatory factors in the bladder.
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Truzzi JC, Gomes CM, Bezerra CA, Plata IM, Campos J, Garrido GL, Almeida FG, Averbeck MA, Fornari A, Salazar A, Dell'Oro A, Cintra C, Sacomani CAR, Tapia JP, Brambila E, Longo EM, Rocha FT, Coutinho F, Favre G, Garcia JA, Castano J, Reyes M, Leyton RE, Ferreira RS, Duran S, Lopez V, Reges R. Overactive bladder - 18 years - Part I. Int Braz J Urol 2017; 42:188-98. [PMID: 27176184 PMCID: PMC4871378 DOI: 10.1590/s1677-5538.ibju.2015.0365] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 09/08/2015] [Indexed: 12/03/2022] Open
Abstract
Abstract: Overactive bladder syndrome is one of the lower urinary tract dysfunctions with the highest number of scientific publications over the past two decades. This shows the growing interest in better understanding this syndrome, which gathers symptoms of urinary urgency and increased daytime and nighttime voiding frequency, with or without urinary incontinence and results in a negative impact on the quality of life of approximately one out of six individuals – including both genders and almost all age groups. The possibility of establishing the diagnosis just from clinical data made patients' access to specialized care easier. Physiotherapy resources have been incorporated into the urological daily practice. A number of more selective antimuscarinic drugs with consequent lower adverse event rates were released. Recently, a new class of oral drugs, beta-adrenergic agonists has become part of the armamentarium for Overactive Bladder. Botulinum toxin injections in the bladder and sacral neuromodulation are routine modalities of treatment for refractory cases. During the 1st Latin-American Consultation on Overactive Bladder, a comprehensive review of the literature related to the evolution of the concept, epidemiology, diagnosis, and management was conducted. This text corresponds to the first part of the review Overactive Bladder 18-years.
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Affiliation(s)
- Jose Carlos Truzzi
- Escola Paulista de Medicina - EPM - Universidade Federal de São Paulo, SP, Brasil
| | | | - Carlos A Bezerra
- Departamento de Urologia, Faculdade de Medicina do ABC, SP, Brasil
| | | | - Jose Campos
- Departamento de Urología, Escuela Médico Militar, Cidade do México, Mexico
| | - Gustavo Luis Garrido
- Cátedra de Urologia, Hospital de Clínicas "José de San Martín", Buenos Aires, Argentina
| | - Fernando G Almeida
- Escola Paulista de Medicina - EPM - Universidade Federal de São Paulo, SP, Brasil
| | | | - Alexandre Fornari
- Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brasil
| | - Anibal Salazar
- Departamento de Urologia, AC Camargo Hospital, SP, Brasil
| | - Arturo Dell'Oro
- Hospital Clinico de la Fuerza Area de Chile, Santiago, Chile
| | - Caio Cintra
- Departamento de Urologia, Faculdade de Medicina do ABC, SP, Brasil
| | | | | | | | - Emilio Miguel Longo
- Servicio de Urología, del Complejo Médico Policial Churruca Visca, Buenos Aires, Argentina
| | | | | | - Gabriel Favre
- Centro Policlínico Valencia "La Viña", Valencia, Venezuela
| | | | | | - Miguel Reyes
- Departamento de Urologia, Hospital Souza Aguiar, RJ, Brasil
| | | | | | - Sergio Duran
- Departamento de Urologia, Hospital Souza Aguiar, RJ, Brasil
| | - Vanda Lopez
- Servicio de Urología, del Hospital Universitario de Caracas, Caracas, Venezuela
| | - Ricardo Reges
- Divisão de Urologia, Universidade Federal do Ceará, CE, Brasil
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Kadekawa K, Yoshizawa T, Wada N, Shimizu T, Majima T, Tyagi P, de Groat WC, Sugaya K, Yoshimura N. Effects of liposome-based local suppression of nerve growth factor in the bladder on autonomic dysreflexia during urinary bladder distention in rats with spinal cord injury. Exp Neurol 2017; 291:44-50. [PMID: 28174025 DOI: 10.1016/j.expneurol.2017.01.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 01/11/2017] [Accepted: 01/31/2017] [Indexed: 12/26/2022]
Abstract
PURPOSE To examine (1) whether spinal cord injury (SCI) time-dependently increases the severity of autonomic dysreflexia (AD) and expression levels of bladder nerve growth factor (NGF) protein, and (2) whether local suppression of NGF in the bladder improves SCI-induced AD in rats. MATERIALS AND METHODS SCI was produced by the transection of the T2/3 spinal cord in female Sprague-Dawley rats. At 4 or 8weeks after SCI, differences in the mean arterial blood pressure (ΔMAP) and heart rate (ΔMHR) during graded increases in intravesical pressure to 20, 40 and 60cm H2O from those before bladder distention and NGF protein levels in the bladder wall were evaluated in spinal intact and SCI rats under urethane anesthesia. Seven weeks after SCI liposome-NGF antisense conjugates were administered intravesically to the animals. At 1week after intravesical treatment (8weeks after SCI), ΔMAP and ΔMHR during bladder distention and bladder NGF protein expression were evaluated. RESULTS The ΔMAP and ΔMHR were increased in a graded manner in response to bladder distention at intravesical pressures of 20, 40 and 60cm H2O in SCI rats. These AD-like cardiovascular responses and NGF protein expression in the bladder mucosal and muscle layers were increased after SCI in a time-dependent manner. The liposome-NGF antisense treatment significantly reduced the NGF protein overexpression in the mucosal layer of SCI rat bladder and reduced ΔMAP and ΔMHR elicited by bladder distention. CONCLUSIONS These results indicate that the duration of the post-SCI recovery period affects the severity of AD induced by bladder distention as well as the level of bladder NGF protein, and that local suppression of NGF expression in the bladder reduces SCI-induced AD. Thus, Intravesical application of liposome-NGF antisense conjugates can be a new effective therapy for bladder distention-induced AD after SCI.
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Affiliation(s)
- Katsumi Kadekawa
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Southern Knights' Laboratory, Okinawa, Japan; Okinawa Kyodo Hospital, Okinawa, Japan
| | - Tsuyoshi Yoshizawa
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Tsuyoshi Majima
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - William C de Groat
- Department of Pharmacology & Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Pharmacology & Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Top T, Sekerci CA, Isbilen-Basok B, Tanidir Y, Tinay I, Isman FK, Akbal C, Simsek F, Tarcan T. The effect of intradetrusor botulinum neurotoxin type A on urinary NGF, TGF BETA-1, TIMP-2 levels in children with neurogenic detrusor overactivity due to myelodysplasia. Neurourol Urodyn 2017; 36:1896-1902. [DOI: 10.1002/nau.23207] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/06/2016] [Indexed: 11/07/2022]
Affiliation(s)
- Tuncay Top
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
| | - Cagri Akin Sekerci
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
| | - Banu Isbilen-Basok
- Deparment of Biochemistry; Tepecik Training and Research Hospital; Izmir Turkey
| | - Yiloren Tanidir
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
| | - Ilker Tinay
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
| | - Ferruh Kemal Isman
- Department of Biochemistry, School of Medicine; Medeniyet University; Istanbul Turkey
| | - Cem Akbal
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
| | - Ferruh Simsek
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
| | - Tufan Tarcan
- Department of Urology; School of Medicine; Marmara University; Istanbul Turkey
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Pathomechanism of Interstitial Cystitis/Bladder Pain Syndrome and Mapping the Heterogeneity of Disease. Int Neurourol J 2016; 20:S95-104. [PMID: 27915472 PMCID: PMC5169097 DOI: 10.5213/inj.1632712.356] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 09/30/2016] [Indexed: 11/26/2022] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous syndrome which is usually characterized by urinary frequency, nocturia, and bladder pain. Several pathomechanisms have been proposed, including uroepithelial dysfunction, mast cell activation, neurogenic inflammation, autoimmunity, and occult urinary tract infections. It is possible that an inflammatory process alters regulation of urothelial homeostasis and results in dysfunction of the bladder epithelium. Different phenotypes of IC/BPS have been explored including Hunner and non-Hunner type IC, hypersensitive bladder, and bladder pain both with and without functional somatic syndrome. Different gene expressions have also been found in different IC phenotypes. Abnormal expressions of uroplakin, chondroitin sulfate and adhesive protein E-cadherin, tight junction protein zonula occludens-1 in IC/BPS bladder suggest abnormal epithelial differentiation in this bladder disease. Analysis of inflammatory proteins, or cytokines in the urine or serum provides another diagnostic foundation forIC/BPS subtypes. The involvement of IC/BPS in systemic functional somatic syndrome and other pelvic organ diseases might also subdivide subtypes of IC/BPS. Chronic inflammation, increased urothelial apoptosis, and abnormal urothelial function are closely associated in IC bladders. This article reviews recent research on the pathomechanisms of IC, which might help us in mapping the heterogeneity of the disease.
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Wada N, Shimizu T, Takai S, Shimizu N, Kanai AJ, Tyagi P, Kakizaki H, Yoshimura N. Post-injury bladder management strategy influences lower urinary tract dysfunction in the mouse model of spinal cord injury. Neurourol Urodyn 2016; 36:1301-1305. [PMID: 27778376 DOI: 10.1002/nau.23120] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 08/24/2016] [Indexed: 12/27/2022]
Abstract
AIMS To examine the effects of a different number of daily bladder squeezes on bladder dysfunction in mice with spinal cord injury (SCI). METHODS Spinal cord was transected at the Th8/9 in female C57BL/6N mice. Their bladders were manually squeezed to eliminate urine inside every day for 4 weeks. The mice were divided into three groups depending on the number of bladder squeezes; A: once daily, B: twice daily, C: three times daily. Four weeks after transection, single-filling cystometry were performed under an awake condition. NGF in the bladder mucosa and mRNA expression of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured. RESULTS Bladder weight in group C was less than that of group A. Bladder capacity, post-void residual, and the number of non-voiding contractions during the storage phase were significantly larger in group A compared to group B or C. The level of NGF in groups C were lower compared to group A or B. The expression of P2X3 and TRPA1 in groups B and C was decreased compared to group A. The expression of P2X2 was decreased in groups B compared to group A. CONCLUSION The post-injury bladder management after SCI with an increased number of daily bladder emptying improves the storage and voiding bladder dysfunction associated with the reduction of NGF in the bladder as well as P2X and TRP transcripts in lumbosacral DRG.
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Affiliation(s)
- Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shun Takai
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nobutaka Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hidehiro Kakizaki
- Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Huang YH, Chang HY, Tsai SW, Chou LW, Chen SL, Lin YH. Comparison of Autonomic Reactions during Urodynamic Examination in Patients with Spinal Cord Injuries and Able-Bodied Subjects. PLoS One 2016; 11:e0161976. [PMID: 27575616 PMCID: PMC5004842 DOI: 10.1371/journal.pone.0161976] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 08/15/2016] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND/PURPOSE This study compares heart rate variability (HRV) and systolic blood pressure (SBP) changes of spinal cord injury (SCI) patients during urodynamic study (UDS) with able-bodied controls. METHODS Twenty four complete suprasacral SCI patients (12 tetraplegia and 12 paraplegia) and 12 age-matched able-bodied volunteers received BP and HRV evaluation throughout urodynamic examination. We chose seven time points during the examinations: resting, Foley catheter insertion, start of infusion, and infused volume reaching 1/4, 2/4, 3/4 and 4/4 of maximal capacity. At each time point, electrocardiogram with a duration of 5 min was used for power spectral density analysis of HRV. RESULTS Only control subjects displayed significant elevation of SBP during Foley catheter insertion compared to resting values. Both control and tetraplegic groups experienced significant elevation of SBP at maximal bladder capacity compared to resting values. Tetraplegic values were also significantly greater than the other two groups. Control subjects displayed significant elevation of low frequency/high frequency (LF/HF) ratios during Foley catheter insertion and when approaching maximum bladder capacity. These findings were not seen in the paraplegic and tetraplegic groups. However, subgroup analysis of tetraplegic subjects with SBP elevation >50 mmHg demonstrated a similar LF/HF response to the able-bodied controls. CONCLUSION Tetraplegic patients experienced BP elevation but did not experience significant changes in HRV during bladder distension. This finding may imply that different neurological pathways contribute to AD reaction and HRV changes during bladder distension. However, profound AD during UDS in tetraplegic patients was associated with corresponding changes in HRV. Whether HRV monitoring would be beneficial in SCI patients presenting with significant AD, it needs further studies to elucidate.
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Affiliation(s)
- Yu-Hui Huang
- Department of Physical Medicine & Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Hsiao-Yun Chang
- School of Physical Therapy, Chung Shan Medical University, Taichung, Taiwan
- Room of Physical Therapy, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Sen-Wei Tsai
- Department of Physical Medicine and Rehabilitation, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Li-Wei Chou
- Department of Physical Medicine and Rehabilitation, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Sung-Lang Chen
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Urology, Chung Shan Medical University Hospital, Taichung, Taiwan
- * E-mail:
| | - Yu-Hao Lin
- Department of Physical Medicine & Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan
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Hu HZ, Granger N, Jeffery ND. Pathophysiology, Clinical Importance, and Management of Neurogenic Lower Urinary Tract Dysfunction Caused by Suprasacral Spinal Cord Injury. J Vet Intern Med 2016; 30:1575-1588. [PMID: 27527382 PMCID: PMC5032886 DOI: 10.1111/jvim.14557] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 06/30/2016] [Accepted: 07/06/2016] [Indexed: 12/24/2022] Open
Abstract
Management of persistent lower urinary tract dysfunction resulting from severe thoracolumbar spinal cord injury can be challenging. Severe suprasacral spinal cord injury releases the spinal cord segmental micturition reflex from supraspinal modulation and increases nerve growth factor concentration in the bladder wall, lumbosacral spinal cord, and dorsal root ganglion, which subsequently activates hypermechanosensitive C-fiber bladder wall afferents. Hyperexcitability of bladder afferents and detrusor overactivity can cause urine leaking during the storage phase. During urine voiding, the loss of supraspinal control that normally coordinates detrusor contraction with sphincter relaxation can lead to spinal cord segmental reflex-mediated simultaneous detrusor and sphincter contractions or detrusor-sphincter dyssynergia, resulting in inefficient urine voiding and high residual volume. These disease-associated changes can impact on the quality of life and life expectancy of spinal-injured animals. Here, we discuss the pathophysiology and management considerations of lower urinary tract dysfunction as the result of severe, acute, suprasacral spinal cord injury. In addition, drawing from experimental, preclinical, and clinical medicine, we introduce some treatment options for neurogenic lower urinary tract dysfunction that are designed to: (1) prevent urine leakage arising because of detrusor overactivity during bladder filling, (2) preserve upper urinary tract integrity and function by reducing intravesical pressure and subsequent vesicoureteral reflux, and (3) prevent urinary tract and systemic complications by treating and preventing urinary tract infections.
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Affiliation(s)
- H Z Hu
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA
| | - N Granger
- School of Veterinary Sciences, University of Bristol, Langford House, Langford, North Somerset, UK
| | - N D Jeffery
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA.
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Jin Y, Bouyer J, Shumsky JS, Haas C, Fischer I. Transplantation of neural progenitor cells in chronic spinal cord injury. Neuroscience 2016; 320:69-82. [PMID: 26852702 DOI: 10.1016/j.neuroscience.2016.01.066] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 01/07/2016] [Accepted: 01/29/2016] [Indexed: 01/24/2023]
Abstract
Previous studies demonstrated that neural progenitor cells (NPCs) transplanted into a subacute contusion injury improve motor, sensory, and bladder function. In this study we tested whether transplanted NPCs can also improve functional recovery after chronic spinal cord injury (SCI) alone or in combination with the reduction of glial scar and neurotrophic support. Adult rats received a T10 moderate contusion. Thirteen weeks after the injury they were divided into four groups and received either: 1. Medium (control), 2. NPC transplants, 3. NPC+lentivirus vector expressing chondroitinase, or 4. NPC+lentivirus vectors expressing chondroitinase and neurotrophic factors. During the 8 weeks post-transplantation the animals were tested for functional recovery and eventually analyzed by anatomical and immunohistochemical assays. The behavioral tests for motor and sensory function were performed before and after injury, and weekly after transplantation, with some animals also tested for bladder function at the end of the experiment. Transplant survival in the chronic injury model was variable and showed NPCs at the injury site in 60% of the animals in all transplantation groups. The NPC transplants comprised less than 40% of the injury site, without significant anatomical or histological differences among the groups. All groups also showed similar patterns of functional deficits and recovery in the 12 weeks after injury and in the 8 weeks after transplantation using the Basso, Beattie, and Bresnahan rating score, the grid test, and the Von Frey test for mechanical allodynia. A notable exception was group 4 (NPC together with chondroitinase and neurotrophins), which showed a significant improvement in bladder function. This study underscores the therapeutic challenges facing transplantation strategies in a chronic SCI in which even the inclusion of treatments designed to reduce scarring and increase neurotrophic support produce only modest functional improvements. Further studies will have to identify the combination of acute and chronic interventions that will augment the survival and efficacy of neural cell transplants.
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Affiliation(s)
- Y Jin
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States.
| | - J Bouyer
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States
| | - J S Shumsky
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States
| | - C Haas
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States
| | - I Fischer
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States.
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Ogawa T, Ishizuka O, Ueda T, Tyagi P, Chancellor MB, Yoshimura N. Current and emerging drugs for interstitial cystitis/bladder pain syndrome (IC/BPS). Expert Opin Emerg Drugs 2015; 20:555-70. [DOI: 10.1517/14728214.2015.1105216] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Tyagi P, Kadekawa K, Kashyap M, Pore S, Yoshimura N. Spontaneous Recovery of Reflex Voiding Following Spinal Cord Injury Mediated by Anti-inflammatory and Neuroprotective Factors. Urology 2015; 88:57-65. [PMID: 26522973 DOI: 10.1016/j.urology.2015.10.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 10/12/2015] [Accepted: 10/15/2015] [Indexed: 12/17/2022]
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 at each time point on controls and 6 SCI animals, and bladder was then harvested for analysis of 29 proteins Millipore kit or enzyme-linked immunosorbent assay. Prophylactic dose of ampicillin 100 mg/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 proinflammatory interleukins ([IL] IL-1α and IL-1β, IL-2, IL-5, IL-6, IL-18, tumor necrosis factor alpha [TNF-α]) and CXC chemokines (CXCL1, CXCL2, CXCL10), CX3CL1, and CCL2 showed significant elevation at 4 and at 8 weeks with slight decrease at 12 weeks. In contrast, expression of anti-inflammatory IL-10 and neuroprotective factors, CXCL-5, and leptin, was elevated at 8 and at 12 weeks (P < .05). In contrast, expression of CCL3, CCL5, and growth factors (vascular endothelial growth factor, nerve growth factor, epidermal growth factor, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor) did not show any significant temporal change after SCI. CONCLUSION Spontaneous recovery of reflex voiding at 12 weeks was marked by increased endogenous expression of anti-inflammatory cytokine IL-10 and neuroprotective factors, CXCL-5, and leptin, which suggests that pharmacological suppression of inflammation, can hasten the emergence of reflex voiding after SCI.
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Affiliation(s)
- Pradeep Tyagi
- Department of Urology, University of Pittsburgh, Pittsburgh, PA.
| | | | | | - Subrata Pore
- Department of Urology, University of Pittsburgh, Pittsburgh, PA
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh, Pittsburgh, PA
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de Groat WC, Yoshimura N. Anatomy and physiology of the lower urinary tract. HANDBOOK OF CLINICAL NEUROLOGY 2015; 130:61-108. [PMID: 26003239 DOI: 10.1016/b978-0-444-63247-0.00005-5] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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.
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Affiliation(s)
- William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Naoki Yoshimura
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Abstract
Spinal cord injury (SCI) results not only in motor and sensory deficits but also in autonomic dysfunctions. The disruption of connections between higher brain centers and the spinal cord, or the impaired autonomic nervous system itself, manifests a broad range of autonomic abnormalities. This includes compromised cardiovascular, respiratory, urinary, gastrointestinal, thermoregulatory, and sexual activities. These disabilities evoke potentially life-threatening symptoms that severely interfere with the daily living of those with SCI. In particular, high thoracic or cervical SCI often causes disordered hemodynamics due to deregulated sympathetic outflow. Episodic hypertension associated with autonomic dysreflexia develops as a result of massive sympathetic discharge often triggered by unpleasant visceral or sensory stimuli below the injury level. In the pelvic floor, bladder and urethral dysfunctions are classified according to upper motor neuron versus lower motor neuron injuries; this is dependent on the level of lesion. Most impairments of the lower urinary tract manifest in two interrelated complications: bladder storage and emptying. Inadequate or excessive detrusor and sphincter functions as well as detrusor-sphincter dyssynergia are examples of micturition abnormalities stemming from SCI. Gastrointestinal motility disorders in spinal cord injured-individuals are comprised of gastric dilation, delayed gastric emptying, and diminished propulsive transit along the entire gastrointestinal tract. As a critical consequence of SCI, neurogenic bowel dysfunction exhibits constipation and/or incontinence. Thus, it is essential to recognize neural mechanisms and pathophysiology underlying various complications of autonomic dysfunctions after SCI. This overview provides both vital information for better understanding these disorders and guides to pursue novel therapeutic approaches to alleviate secondary complications.
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Affiliation(s)
- Shaoping Hou
- Spinal Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
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Sacco E, Recupero S, Bientinesi R, Palermo G, D’Agostino D, Currò D, Bassi P. Pioneering drugs for overactive bladder and detrusor overactivity: Ongoing research and future directions. World J Obstet Gynecol 2015; 4:24-39. [DOI: 10.5317/wjog.v4.i2.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 01/31/2015] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
The ongoing research on pioneering drug candidates for the overactive bladder (OAB) aimed to overcome the limitations of currently licensed pharmacotherapies, such as antimuscarinics, β3-adrenergic agents, and botulinum neurotoxin, has been reviewed performing a systematic literature review and web search. The review covers the exploratory agents alternative to available medications for OAB and that may ultimately prove to be therapeutically useful in the future management of OAB patients based on preclinical and early clinical data. It emerges that many alternative pharmacological strategies have been discovered or are under investigation in disease-oriented studies. Several potential therapeutics are known for years but still find obstacles to pass the clinical stages of development, while other completely novel compounds, targeting new pharmacological targets, have been recently discovered and show potential to translate into clinical therapeutic agents for idiopathic and neurogenic OAB syndrome. The global scenario of investigational drugs for OAB gives promise for the development of innovative therapeutics that may ultimately prove effective as first, combined or second-line treatments within a realistic timescale of ten years.
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Cho YS, Ko IG, Kim CJ, Kim KH. A novel intracerebral hemorrhage-induced rat model of neurogenic voiding dysfunction: Analysis of lower urinary tract function. Mol Med Rep 2015; 12:2563-9. [PMID: 25954993 PMCID: PMC4464363 DOI: 10.3892/mmr.2015.3720] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 09/18/2014] [Indexed: 01/27/2023] Open
Abstract
Neurogenic lower urinary tract dysfunction (NLUTD) is a major problem in patients with various neurological disorders, and may result in debilitating symptoms and serious complications, including chronic renal failure and recurrent urinary tract infections. Clinically, stroke is associated with voiding dysfunction. However, lower urinary tract function evaluation in an intracerebral hemorrhage (ICH) model has not, to the best of our knowledge, been reported. Therefore, in the present study, lower urinary tract function in ICH-induced rats was investigated and the results were compared with those obtained in normal rats. The effects of ICH on peripheral bladder function and central micturition centers [medial preoptic area, ventrolateral gray, pontaine micturition center and spinal cord (lumbar 4 (L4)-L5)] were also examined. Adult female Sprague-Dawley rats were divided into two groups: Control ICH-induced. Induction of ICH in the hippocampal CA1 region was performed using a stereotaxic frame and type IV collagenase. The effects of ICH on the central micturition centers were investigated by simultaneously determining the extent of neuronal activation (c-Fos) and nerve growth factor (NGF) expression, and assessing voiding function (urodynamically using cystometry). The results revealed that induction of ICH significantly enhanced bladder contraction pressure and time, while simultaneously reducing voiding pressure and time. Furthermore, the c-Fos and NGF expression levels in the neuronal voiding centers were significantly increased in the rats with induced ICH as compared with the control rats. Therefore, this ICH-induced NLUTD rat model may be a more appropriate method to analyze NLUTD in stroke patients than a cerebral infarction model, as the former more accurately reflects the nature of the hemorrhage in the two types of stroke.
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Affiliation(s)
- Young-Sam Cho
- Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110‑746, Republic of Korea
| | - Il-Gyu Ko
- Department of Physiology, Kyung Hee University College of Medicine, Seoul 130‑701, Republic of Korea
| | - Chang-Ju Kim
- Department of Physiology, Kyung Hee University College of Medicine, Seoul 130‑701, Republic of Korea
| | - Khae-Hawn Kim
- Department of Urology, Gachon University School of Medicine, Gil Medical Center, Incheon 405‑760, Republic of Korea
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47
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Yoshimura N, Oguchi T, Yokoyama H, Funahashi Y, Yoshikawa S, Sugino Y, Kawamorita N, Kashyap MP, Chancellor MB, Tyagi P, Ogawa T. Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis. Int J Urol 2015; 21 Suppl 1:18-25. [PMID: 24807488 DOI: 10.1111/iju.12308] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 08/27/2013] [Indexed: 12/30/2022]
Abstract
Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis.
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Affiliation(s)
- Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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48
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Herrity AN, Petruska JC, Stirling DP, Rau KK, Hubscher CH. The effect of spinal cord injury on the neurochemical properties of vagal sensory neurons. Am J Physiol Regul Integr Comp Physiol 2015; 308:R1021-33. [PMID: 25855310 DOI: 10.1152/ajpregu.00445.2014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 04/01/2015] [Indexed: 12/29/2022]
Abstract
The vagus nerve is composed primarily of nonmyelinated sensory neurons whose cell bodies are located in the nodose ganglion (NG). The vagus has widespread projections that supply most visceral organs, including the bladder. Because of its nonspinal route, the vagus nerve itself is not directly damaged from spinal cord injury (SCI). Because most viscera, including bladder, are dually innervated by spinal and vagal sensory neurons, an impact of SCI on the sensory component of vagal circuitry may contribute to post-SCI visceral pathologies. To determine whether SCI, in male Wistar rats, might impact neurochemical characteristics of NG neurons, immunohistochemical assessments were performed for P2X3 receptor expression, isolectin B4 (IB4) binding, and substance P expression, three known injury-responsive markers in sensory neuronal subpopulations. In addition to examining the overall population of NG neurons, those innervating the urinary bladder also were assessed separately. All three of the molecular markers were represented in the NG from noninjured animals, with the majority of the neurons binding IB4. In the chronically injured rats, there was a significant increase in the number of NG neurons expressing P2X3 and a significant decrease in the number binding IB4 compared with noninjured animals, a finding that held true also for the bladder-innervating population. Overall, these results indicate that vagal afferents, including those innervating the bladder, display neurochemical plasticity post-SCI that may have implications for visceral homeostatic mechanisms and nociceptive signaling.
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Affiliation(s)
- April N Herrity
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky; Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky
| | - Jeffrey C Petruska
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky; Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky; Department of Neurological Surgery, University of Louisville, Louisville, Kentucky
| | - David P Stirling
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky; Department of Neurological Surgery, University of Louisville, Louisville, Kentucky; Department of Microbiology & Immunology, University of Louisville School of Medicine, Louisville, Kentucky; and
| | - Kristofer K Rau
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky; Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky; Department of Anesthesiology, University of Louisville, Louisville, Kentucky
| | - Charles H Hubscher
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky; Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky;
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49
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Chapple C. Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder". Neurourol Urodyn 2015; 33 Suppl 3:S6-13. [PMID: 25042142 DOI: 10.1002/nau.22635] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 04/18/2014] [Indexed: 01/23/2023]
Abstract
It is now clearly recognized that the function of the lower urinary tract represents a complex interaction between the bladder and its outlet, acting under the control of the central nervous system. While in the past attention has principally focused on the motor (efferent) control of the bladder, sensory (afferent) innervation is now known to be an important therapeutic target. This change in emphasis is strongly supported by both basic science and clinical evidence demonstrating the efficacy of therapy directed at the afferent system. This chapter summarizes the neurophysiological control mechanism that underpins normal lower urinary tract function, emphasizing the importance of the afferent system as a potential therapeutic target.
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Affiliation(s)
- Christopher Chapple
- The Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, United Kingdom
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50
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Chung HC, Lee CK, Park KH, Jeong SW. Bladder outlet obstruction causes up-regulation of nicotinic acetylcholine receptors in bladder-projecting pelvic ganglion neurons. Brain Res 2015; 1602:111-8. [PMID: 25625357 DOI: 10.1016/j.brainres.2015.01.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/09/2015] [Accepted: 01/16/2015] [Indexed: 12/21/2022]
Abstract
Pelvic ganglion (PG) neurons relay sympathetic and parasympathetic signals to the lower urinary tract, comprising the urinary bladder and bladder outlet, and are thus essential for both storage and voiding reflexes. Autonomic transmission is mediated by activation of the nicotinic acetylcholine receptor (nAChR) in PG neurons. Previously, bladder outlet obstruction (BOO), secondary to benign prostatic hyperplasia, was found to increase soma sizes of bladder-projecting PG neurons. To date, however, it remains unknown whether these morphological changes are accompanied by functional plasticity in PG neurons. In the present study, we investigated whether BOO alters acetylcholine receptor (nAChR) transcript expression and current density in bladder PG neurons. Partial ligation of the rat urethra for six weeks induced detrusor overactivity (DO), as observed during cystometrical measurement. In rats exhibiting DO, membrane capacitance of parasympathetic bladder PG neurons was selectively increased. Real-time PCR analysis revealed that BOO enhanced the expression of the transcripts encoding the nAChR α3 and β4 subunits in PG neurons. Notably, BOO significantly increased ACh-evoked current density in parasympathetic bladder PG neurons, whereas no changes were observed in sympathetic bladder and parasympathetic penile PG neurons. In addition, other ligand-gated ionic currents were immune to BOO in bladder PG neurons. Taken together, these data suggest that BOO causes upregulation of nAChR in parasympathetic bladder PG neurons, which in turn may potentiate ganglionic transmission and contribute to the development of DO.
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Affiliation(s)
- Hyun-Chul Chung
- Department of Urology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
| | - Choong-Ku Lee
- Department of Physiology, Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
| | - Kwang-Hwa Park
- Department of Pathology, Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
| | - Seong-Woo Jeong
- Department of Physiology, Brain Research Group, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
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