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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (10 June 2023) | Viewed by 23404

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Special Issue Editor

Prof. Dr. Thomas M. Kessler

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Department of Neuro-Urology, Balgrist University Hospital, University of Zürich, Forchstrasse 340, 8008 Zürich, Switzerland
Interests: neuro-urology; functional urology; urinary tract infections
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurogenic lower urinary tract, sexual, and bowel dysfunction is highly prevalent and affects the life of millions of people worldwide. It not only has a major impact on quality of life but also imposes a substantial economic burden on every healthcare system.

The control of lower urinary tract function is a complex, multilevel central and peripheral process with a neural network distributed across parasympathetic, sympathetic, and somatic pathways. It is therefore not surprising that many neurological disorders such as multiple sclerosis, Parkinson’s disease, stroke, spinal cord injury, spina bifida, diabetic neuropathy, Alzheimer’s disease, etc. frequently result in lower urinary tract, sexual and bowel dysfunction. The location and extent of the lesion in the neurological axis determines the dysfunction pattern, which is reflected in the patient’s symptoms. Indeed, the variability of neurogenic lower urinary tract dysfunction is huge and may range from a completely asymptomatic situation upon end-stage renal failure requiring hemodialysis. In addition, the prevalence and incidence of several neurological disorders are already high, and neurodegenerative disorders such as Alzheimer’s disease will further increase in the course of a continuously aging population so that more and more neurological patients will require professional neuro-urological management. This, however, can only be provided by adequately trained clinicians and enthusiastic researchers since many questions regarding the neural control of lower urinary tract, sexual, and bowel function and its alterations through the course of a neurological disorder remain unclear.

This Special Issue of the International Journal of Molecular Sciences (IJMS) focuses on the molecular level of mechanisms involved in neuro-urology and welcomes both original research articles and review papers.

Prof. Dr. Thomas M. Kessler
Guest Editor

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Keywords

Neuro-urology
Neurogenic lower urinary tract dysfunction
Neurogenic sexual dysfunction
Neurogenic bowel dysfunction
Neurological disorders
Pathomechanisms
Molecular level

Published Papers (13 papers)

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Research

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12 pages, 1823 KiB

Open AccessArticle

Mechanism of Social Stress-Related Erectile Dysfunction in Mice: Impaired Parasympathetic Neurotransmission and Ketamine

by Shu-Yu Wu, Tze-Chen Chao, Chun-Kai Hsu, His-Hsien Chang and Stephen Shei-Dei Yang

Int. J. Mol. Sci. 2023, 24(15), 11973; https://doi.org/10.3390/ijms241511973 - 26 Jul 2023

Viewed by 978

Abstract

This study aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single subanesthetic dose of ketamine on SS-related ED. Male FVB mice were exposed to retired male C57BL/6 mice for 60 min daily over a 4-week period. In the third week, these FVB mice received intraperitoneal injections of either saline (SSS group) or ketamine (SSK group). Erectile function was assessed by measuring the intracavernosal pressure (ICP) during electrical stimulation of the major pelvic ganglia. Corpus cavernosum (CC) strips were utilized for wire myography to assess their reactivity. Both SSS and SSK mice exhibited significantly lower ICP in response to electrical stimulation than control mice. SS mice showed increased contractility of the CC induced by phenylephrine. Acetylcholine-induced relaxation was significantly reduced in SSS and SSK mice. Sodium nitroprusside-induced relaxation was higher in SSS mice compared to control and SSK mice. Nicotine-induced neurogenic and nitric oxide-dependent relaxation was significantly impaired in both SSS and SSK mice. An immunohistochemical analysis revealed co-localization of tyrosine hydroxylase and neuronal nitric oxide synthase-immunoreactive fibers in the CC. These findings highlight the complex nature of SS-related ED and suggest the limited efficacy of ketamine as a therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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15 pages, 3406 KiB

Open AccessArticle

Myostatin Overexpression and Smad Pathway in Detrusor Derived from Pediatric Patients with End-Stage Lower Urinary Tract Dysfunction

by Souzan Salemi, Larissa J. Schori, Tim Gerwinn, Maya Horst and Daniel Eberli

Int. J. Mol. Sci. 2023, 24(5), 4462; https://doi.org/10.3390/ijms24054462 - 24 Feb 2023

Cited by 1 | Viewed by 1624

Abstract

Cell therapies and tissue engineering approaches using smooth muscle cells (SMCs) may provide treatment alternatives for end-stage lower urinary tract dysfunction (ESLUTD). Myostatin, a negative regulator of muscle mass, is a promising target to improve muscle function through tissue engineering. The ultimate goal of our project was to investigate the expression of myostatin and its potential impact in SMCs derived from healthy pediatric bladders and pediatric ESLUTD patients. Human bladder tissue samples were evaluated histologically, and SMCs were isolated and characterized. The proliferation of SMCs was assessed by WST-1 assay. The expression pattern of myostatin, its pathway and the contractile phenotype of the cells were investigated at gene and protein levels by real-time PCR, flow cytometry, immunofluorescence, WES and gel contraction assay. Our results show that myostatin is expressed in human bladder smooth muscle tissue and in isolated SMCs at gene and protein levels. A higher expression of myostatin was detected in ESLUTD-derived compared to control SMCs. Histological assessment of bladder tissue confirmed structural changes and decreased muscle-to-collagen ratios in ESLUTD bladders. A decrease in cell proliferation and in the expression of key contractile genes and proteins, α-SMA, calponin, smoothelin and MyH11, as well as a lower degree of in vitro contractility was observed in ESLUTD-derived compared to control SMCs. A reduction in the myostatin-related proteins Smad 2 and follistatin, and an upregulation in the proteins p-Smad 2 and Smad 7 were observed in ESLUTD SMC samples. This is the first demonstration of myostatin expression in bladder tissue and cells. The increased expression of myostatin and the changes in the Smad pathways were observed in ESLUTD patients. Therefore, myostatin inhibitors could be considered for the enhancement of SMCs for tissue engineering applications and as a therapeutic option for patients with ESLUTD and other smooth muscle disorders. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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15 pages, 4408 KiB

Open AccessArticle

Involvement of Mast-Cell-Tryptase- and Protease-Activated Receptor 2—Mediated Signaling and Urothelial Barrier Dysfunction with Reduced Uroplakin II Expression in Bladder Hyperactivity Induced by Chronic Bladder Ischemia in the Rat

by Hidenori Akaihata, Kanako Matsuoka, Junya Hata, Yuki Harigane, Kei Yaginuma, Yu Endo, Hitomi Imai, Yuta Matsuoka, Akifumi Onagi, Ryo Tanji, Ruriko Honda-Takinami, Seiji Hoshi, Tomoyuki Koguchi, Yuichi Sato, Masao Kataoka, Motohide Uemura, Yasuhiko Igawa and Yoshiyuki Kojima

Int. J. Mol. Sci. 2023, 24(4), 3982; https://doi.org/10.3390/ijms24043982 - 16 Feb 2023

Cited by 1 | Viewed by 1144

Abstract

We aimed to investigate the relationship between mast cell (MC) infiltration into the bladder with urothelial barrier dysfunction and bladder hyperactivity in a chronic bladder ischemia (CBI) rat model. We compared CBI rats (CBI group; n = 10) with normal rats (control group; n = 10). We measured the expression of mast cell tryptase (MCT) and protease-activated receptor 2 (PAR2), which are correlated with C fiber activation via MCT, and Uroplakins (UP Ia, Ib, II and III), which are critical to urothelial barrier function, via Western blotting. The effects of FSLLRY-NH2, a PAR2 antagonist, administered intravenously, on the bladder function of CBI rats were evaluated with a cystometrogram. In the CBI group, the MC number in the bladder was significantly greater (p = 0.03), and the expression of MCT (p = 0.02) and PAR2 (p = 0.02) was significantly increased compared to that of the control group. The 10 μg/kg FSLLRY-NH2 injection significantly increased the micturition interval of CBI rats (p = 0.03). The percentage of UP-II-positive cells on the urothelium with immunohistochemical staining was significantly lower in the CBI group than in the control group (p < 0.01). Chronic ischemia induces urothelial barrier dysfunction via impairing UP II, consequently inducing MC infiltration into the bladder wall and increased PAR2 expression. PAR2 activation by MCT may contribute to bladder hyperactivity. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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21 pages, 11478 KiB

Open AccessArticle

Molecular Characterization of Non-Neurogenic and Neurogenic Lower Urinary Tract Dysfunction (LUTD) in SCI-Induced and Partial Bladder Outlet Obstruction Mouse Models

by Michelle von Siebenthal, Akshay Akshay, Mustafa Besic, Marc P. Schneider, Ali Hashemi Gheinani, Fiona C. Burkhard and Katia Monastyrskaya

Int. J. Mol. Sci. 2023, 24(3), 2451; https://doi.org/10.3390/ijms24032451 - 26 Jan 2023

Cited by 2 | Viewed by 1515

Abstract

We examined bladder function following spinal cord injury (SCI) by repeated urodynamic investigation (UDI), including external urethral sphincter (EUS) electromyography (EMG) in awake restrained mice and correlated micturition parameters to gene expression and morphological changes in the bladder. A partial bladder outlet obstruction (pBOO) model was used for comparison to elucidate both the common and specific features of obstructive and neurogenic lower urinary tract dysfunction (LUTD). Thirty female C57Bl/6J mice in each group received an implanted bladder catheter with additional electrodes placed next to the EUS in the SCI group. UDI assessments were performed weekly for 7 weeks (pBOO group) or 8 weeks (SCI group), after which bladders were harvested for histological and transcriptome analysis. SCI mice developed detrusor sphincter dyssynergia (DSD) one week after injury with high-pressure oscillations and a significantly increased maximal bladder pressure P_max and were unable to void spontaneously during the whole observation period. They showed an increased bladder-to-bodyweight ratio, bladder fibrosis, and transcriptome changes indicative of extracellular matrix remodeling and alterations of neuronal signaling and muscle contraction. In contrast, pBOO led to a significantly increased P_max after one week, which normalized at later time points. Increased bladder-to-bodyweight ratio and pronounced gene expression changes involving immune and inflammatory pathways were observed 7 weeks after pBOO. Comparative transcriptome analysis of SCI and pBOO bladders revealed the activation of Wnt and TGF-beta signaling in both the neurogenic and obstructive LUTD and highlighted FGF2 as a major upregulated transcription factor during organ remodeling. We conclude that SCI-induced DSD in mice leads to profound changes in neuronal signaling and muscle contractility, leading to bladder fibrosis. In a similar time frame, significant bladder remodeling following pBOO allowed for functional compensation, preserving normal micturition parameters. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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19 pages, 4081 KiB

Open AccessArticle

Spinal Cord Injury Causes Marked Tissue Rearrangement in the Urethra—Experimental Study in the Rat

by Ana Ferreira, Sílvia Sousa Chambel, António Avelino and Célia Duarte Cruz

Int. J. Mol. Sci. 2022, 23(24), 15951; https://doi.org/10.3390/ijms232415951 - 15 Dec 2022

Viewed by 1624

Abstract

Traumatic spinal cord injury (SCI) results in the time-dependent development of urinary impairment due to neurogenic detrusor overactivity (NDO) and detrusor-sphincter-dyssynergia (DSD). This is known to be accompanied by massive changes in the bladder wall. It is presently less clear if the urethra wall also undergoes remodelling. To investigate this issue, female rats were submitted to complete spinal transection at the T8/T9 level and left to recover for 1 week and 4 weeks. To confirm the presence of SCI-induced NDO, bladder function was assessed by cystometry under urethane anesthesia before euthanasia. Spinal intact animals were used as controls. Urethras were collected and processed for further analysis. Following thoracic SCI, time-dependent changes in the urethra wall were observed. Histological assessment revealed marked urethral epithelium reorganization in response to SCI, as evidenced by an increase in epithelial thickness. At the muscular layer, SCI resulted in strong atrophy of the smooth muscle present in the urethral sphincter. Innervation was also affected, as evidenced by a pronounced decrease in the expression of markers of general innervation, particularly those present in sensory and sympathetic nerve fibres. The present data show an evident impact of SCI on the urethra, with significant histological rearrangement, accompanied by sensory and sympathetic denervation. It is likely that these changes will affect urethral function and contribute to SCI-induced urinary dysfunction, and they deserve further investigation. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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14 pages, 3102 KiB

Open AccessArticle

Effect of Bladder Injection of OnabotulinumtoxinA on the Central Expression of Genes Associated with the Control of the Lower Urinary Tract: A Study in Normal Rats

by Soultana Markopoulou, Lina Vardouli, Fotios Dimitriadis, Dimitra Psalla, Alexandros Lambropoulos and Apostolos Apostolidis

Int. J. Mol. Sci. 2022, 23(22), 14419; https://doi.org/10.3390/ijms232214419 - 20 Nov 2022

Cited by 2 | Viewed by 1239

Abstract

To investigate a possible central mechanism of action of Botulinum toxin A (BoNT/A) following injection in the bladder, complementary to the acknowledged peripheral bladder effect, we studied changes in the expression of neuropeptides and receptors involved in lower urinary tract function in the spinal cord (SC) and dorsal root ganglia (DRG) of normal rats following BoNT/A bladder injection. Thirty-six Sprague-Dawley rats, divided into three groups of n = 12, received bladder injections of 2U or 5U OnabotulinumtoxinA (BOTOX^®), or saline. Six animals from each group were sacrificed on days 7 and 14. Expression of Tachykinin 1 (Tac1), capsaicin receptor (TRPV1), neuropeptide Y (NPY), proenkephalin (PENK) and muscarinic receptors M1, M2, M3, was evaluated in the bladder, L6-S1 DRG, and SC segments using real-time PCR and Western blotting. Real-time PCR revealed increased expression of NPY in all tissues except for SC, and increased TRPV1 and PENK expression in DRG and SC, whereas expression of Tac1, M1 and M2 was decreased. Less significant changes were noted in protein levels. These findings suggest that bladder injections of OnabotulinumtoxinA may be followed by changes in the expression of sensory, sympathetic and cholinergic bladder function regulators at the DRG/SC level. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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12 pages, 3187 KiB

Open AccessArticle

Molecular and Morphological Characteristics of the De-Obstructed Rat Urinary Bladder—An Update

by Bengt Uvelius and Karl-Erik Andersson

Int. J. Mol. Sci. 2022, 23(19), 11330; https://doi.org/10.3390/ijms231911330 - 26 Sep 2022

Cited by 3 | Viewed by 1189

Abstract

Many patients with outlet obstruction secondary to prostatic enlargement have lower urinary tract symptoms (LUTSs) and an increased frequency of micturition. The standard treatment is transurethral resection of the prostate (TURP), which alleviates obstruction and symptoms. However, after TURP, 20–40 percent of patients continue to experience LUTSs. The aim of the present study in rats was to identify the mechanisms that do not normalize after the removal of the obstruction and that could explain the persisting symptoms. We had microarray data from control, obstructed, and de-obstructed female rat bladders, which made it possible to study 14,553 mRNA expressions. We also had a bank of electron micrographs from similar detrusors. Microarrays: There were significant differences between the control and obstructed bladders for 1111 mRNAs. The obstructed and de-obstructed bladders differed significantly for 1059 mRNAs. The controls and the de-obstructed bladders differed significantly for 798 mRNAs. We observed many mRNAs that were increased in the obstructed bladder and then decreased to control levels after de-obstruction, and many mRNAs that were decreased in the obstructed bladder and then increased following de-obstruction. mRNAs that were significantly higher or lower in the de-obstructed bladder than in the control bladder were also found. Ultrastructure: The detrusor cells in the obstructed bladders had cross-sectional areas that were much larger than those in the controls. The control cells had smooth outlines and similar cross-sectional areas. The de-obstructed detrusor cells had larger cross-sectional areas than the controls, as well as corrugated surfaces. The cell areas varied, suggesting that the shrinkage of the de-obstructed cells was not even. We did not find any points of contact of the gap junction plaque type between the detrusor cells. There were abundant finger-like processes between the detrusor cells in the obstructed and in de-obstructed bladders, which were only occasionally found in the control detrusors. They are the only possible localization for gap junction channels. The de-obstructed rat bladder is not an organ with properties intermediate between those of the control and obstructed bladders. Instead, de-obstructed bladders have gene expressions, morphologies, and functional properties of the individual cells and their organization, which make them distinctly different from both control and obstructed bladders. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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12 pages, 2082 KiB

Open AccessArticle

Development and Assessment of Herpes Simplex Virus Type 1 (HSV-1) Amplicon Vectors with Sensory Neuron-Selective Promoters

by Charles Joussain, Olivier Le Coz, Andrey Pichugin, Peggy Marconi, Filip Lim, Mariaconcetta Sicurella, Keith Foster, François Giuliano, Alberto L. Epstein and Alejandro Aranda Muñoz

Int. J. Mol. Sci. 2022, 23(15), 8474; https://doi.org/10.3390/ijms23158474 - 30 Jul 2022

Viewed by 2232

Abstract

Background: Neurogenic detrusor overactivity (NDO) is a severe pathological condition characterized by involuntary detrusor contractions leading to urine leakage. This condition is frequent after spinal cord injury (SCI). Gene therapy for NDO requires the development of vectors that express therapeutic transgenes driven by sensory neuron-specific promoters. The aim of this study was to develop and assess tools for the characterization of sensory neuron-specific promoters in dorsal root ganglia (DRG) neurons after transduction with herpes simplex virus type 1 (HSV-1)-based amplicon defective vectors. Methods: The HSV-1 vector genome encoded two independent transcription cassettes: one expressed firefly luciferase (FLuc) driven by different promoters’ candidates (rTRPV1, rASIC3, rCGRP, or hCGRP), and the other expressed a reporter gene driven by an invariable promoter. The strength and selectivity of promoters was assessed in organotypic cultures of explanted adult DRG, or sympathetic and parasympathetic ganglia from control and SCI rats. Results: The rCGRP promoter induced selective expression in the DRG of normal rats. The rTRPV-1 promoter, which did not display selective activity in control rats, induced selective expression in DRG explanted from SCI rats. Conclusions: This study provides a methodology to assess sensory neuron-specific promoters, opening new perspectives for future gene therapy for NDO. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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Review

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17 pages, 654 KiB

Open AccessReview

Neuro-Urology and Biobanking: An Integrated Approach for Advancing Research and Improving Patient Care

by Sander M. Botter and Thomas M. Kessler

Int. J. Mol. Sci. 2023, 24(18), 14281; https://doi.org/10.3390/ijms241814281 - 19 Sep 2023

Viewed by 1110

Abstract

Understanding the molecular mechanisms underlying neuro-urological disorders is crucial for the development of targeted therapeutic interventions. Through the establishment of comprehensive biobanks, researchers can collect and store various biological specimens, including urine, blood, tissue, and DNA samples, to study these mechanisms. In the context of neuro-urology, biobanking facilitates the identification of genetic variations, epigenetic modifications, and gene expression patterns associated with neurogenic lower urinary tract dysfunction. These conditions often present as symptoms of neurological diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, spinal cord injury, and many others. Biobanking of tissue specimens from such patients is essential to understand why these diseases cause the respective symptoms and what can be done to alleviate them. The utilization of high-throughput technologies, such as next-generation sequencing and gene expression profiling, enables researchers to explore the molecular landscape of these conditions in an unprecedented manner. The development of specific and reliable biomarkers resulting from these efforts may help in early detection, accurate diagnosis, and effective monitoring of neuro-urological conditions, leading to improved patient care and management. Furthermore, these biomarkers could potentially facilitate the monitoring of novel therapies currently under investigation in neuro-urological clinical trials. This comprehensive review explores the synergistic integration of neuro-urology and biobanking, with particular emphasis on the translation of biobanking approaches in molecular research in neuro-urology. We discuss the advantages of biobanking in neuro-urological studies, the types of specimens collected and their applications in translational research. Furthermore, we highlight the importance of standardization and quality assurance when collecting samples and discuss challenges that may compromise sample quality and impose limitations on their subsequent utilization. Finally, we give recommendations for sampling in multicenter studies, examine sustainability issues associated with biobanking, and provide future directions for this dynamic field. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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17 pages, 1506 KiB

Open AccessReview

Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury

by Nobutaka Shimizu, Tetsuichi Saito, Naoki Wada, Mamoru Hashimoto, Takahiro Shimizu, Joonbeom Kwon, Kang Jun Cho, Motoaki Saito, Sergei Karnup, William C. de Groat and Naoki Yoshimura

Int. J. Mol. Sci. 2023, 24(9), 7885; https://doi.org/10.3390/ijms24097885 - 26 Apr 2023

Cited by 7 | Viewed by 2170

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. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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15 pages, 719 KiB

Open AccessReview

Neurogenic Lower Urinary Tract Dysfunction in Spinal Dysraphism: Morphological and Molecular Evidence in Children

by Dafni Planta, Tim Gerwinn, Souzan Salemi and Maya Horst

Int. J. Mol. Sci. 2023, 24(4), 3692; https://doi.org/10.3390/ijms24043692 - 12 Feb 2023

Cited by 2 | Viewed by 2170

Abstract

Spinal dysraphism, most commonly myelomeningocele, is the typical cause of a neurogenic lower urinary tract dysfunction (NLUTD) in childhood. The structural changes in the bladder wall in spinal dysraphism already occur in the fetal period and affect all bladder wall compartments. The progressive decrease in smooth muscle and the gradual increase in fibrosis in the detrusor, the impairment of the barrier function of the urothelium, and the global decrease in nerve density, lead to severe functional impairment characterized by reduced compliance and increased elastic modulus. Children present a particular challenge, as their diseases and capabilities evolve with age. An increased understanding of the signaling pathways involved in lower urinary tract development and function could also fill an important knowledge gap at the interface between basic science and clinical implications, leading to new opportunities for prenatal screening, diagnosis, and therapy. In this review, we aim to summarize the evidence on structural, functional, and molecular changes in the NLUTD bladder in children with spinal dysraphism and discuss possible strategies for improved management and for the development of new therapeutic approaches for affected children. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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41 pages, 1396 KiB

Open AccessReview

Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin

by Ana Ferreira, Diogo Nascimento and Célia Duarte Cruz

Int. J. Mol. Sci. 2023, 24(4), 3273; https://doi.org/10.3390/ijms24043273 - 07 Feb 2023

Cited by 1 | Viewed by 2246

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. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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27 pages, 2848 KiB

Open AccessReview

Why Are Some People with Lower Urinary Tract Symptoms (LUTS) Depressed? New Evidence That Peripheral Inflammation in the Bladder Causes Central Inflammation and Mood Disorders

by Francis M. Hughes, Jr., Michael R. Odom, Anissa Cervantes, Austin J. Livingston and J. Todd Purves

Int. J. Mol. Sci. 2023, 24(3), 2821; https://doi.org/10.3390/ijms24032821 - 01 Feb 2023

Cited by 6 | Viewed by 2901

Abstract

Anecdotal evidence has long suggested that patients with lower urinary tract symptoms (LUTS) develop mood disorders, such as depression and anxiety, at a higher rate than the general population and recent prospective studies have confirmed this link. Breakthroughs in our understanding of the diseases underlying LUTS have shown that many have a substantial inflammatory component and great strides have been made recently in our understanding of how this inflammation is triggered. Meanwhile, studies on mood disorders have found that many are associated with central neuroinflammation, most notably in the hippocampus. Excitingly, work on other diseases characterized by peripheral inflammation has shown that they can trigger central neuroinflammation and mood disorders. In this review, we discuss the current evidence tying LUTS to mood disorders, its possible bidirectionally, and inflammation as a common mechanism. We also review modern theories of inflammation and depression. Finally, we discuss exciting new animal studies that directly tie two bladder conditions characterized by extensive bladder inflammation (cyclophosphamide-induced hemorrhagic cystitis and bladder outlet obstruction) to neuroinflammation and depression. We conclude with a discussion of possible mechanisms by which peripheral inflammation is translated into central neuroinflammation with the resulting psychiatric concerns. Full article

(This article belongs to the Special Issue Molecular Research in Neuro-Urology)

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