Efficacy of vibegron, a novel β3‐adrenoreceptor agonist, for lower urinary tract dysfunction in mice with spinal cord injury

Shimizu, Nobuyoshi; Gotoh, Daisuke; Nishimoto, Mitsuhisa; Hashimoto, Mamoru; Saito, Tetsuichi; Fujita, Kazutoshi; Hirayama, Akihide; Yoshimura, Naoki; Uemura, Hirotsugu

doi:10.1111/iju.14630

Cited by 9 publications

(11 citation statements)

References 22 publications

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“…The vast majority of the analyzed reports, 74%, use spinal cord injury as an NDO model ( Figure 2 B). From these publications, 59% report complete transection of thoracic segments to induce SCI [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 38 , 39 , 43 , 44 , 46 , 48 , 49 , 50 , 55 , 57 , 62 , 63 ], followed by spinal contusion (13%). The use of spinal hemisections was less frequent (10%) [ 42 , 47 , 52 ], as were spinal compressions (8%) [ 32 , 36 , 54 , 56 ] and other SCI methods (10%) [ 41 , 51 , 53 , 58 ] ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Most of the studies reporting urodynamic recordings used awake cystometry as the recording method (37%) [ 31 , 32 , 33 , 34 , 35 , 38 , 39 , 42 , 46 , 47 , 48 , 52 , 56 , 59 , 63 , 68 , 70 , 71 ]. Cystometry under anesthesia represented 26% of studies, with 16% using urethane delivered via subcutaneous [ 26 , 27 , 28 , 37 , 41 , 43 , 51 ] or intraperitoneal injection [ 57 ], 8% using zolotyl [ 53 , 58 , 61 , 74 ], and 2% referring the use of chloral hydrate as anesthetic [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

“…However, this is not the case when it comes to urological investigations. The majority of the retrieved articles in our systematic study used complete transection models [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 38 , 39 , 43 , 44 , 46 , 48 , 49 , 50 , 55 , 57 , 62 , 63 ] (58%), which may be explained by their ease of reproduction and the lower associated costs, as they do not require specific equipment. One could speculate that, when it comes to studying SCI-induced urinary dysfunction, the chosen method to reproduce SCI is not as important as it is in regenerative or tissue engineering studies.…”

Section: Discussionmentioning

confidence: 99%

“…We found two contradictory perspectives on the expression of P2X purinergic receptors and TRP channel expression in SCI animals. Concerning the expression of these receptors in DRG cells, four studies [ 35 , 46 , 49 , 63 ] reported upregulation of TRP and P2X receptors, while another study [ 45 ] reported TRP/P2X pathway elements’ downregulation. Similarly, in the bladder, three studies [ 30 , 51 , 56 ] showed upregulation of TRP and P2X elements, while one reported downregulation [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

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

Ferreira

Nascimento

Cruz

2023

IJMS

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Ferreira

Nascimento

Cruz

2023

IJMS

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“…Cardiac function [369] Micturition [370], locomotor recovery [371,372], cardiac function [369] β 2 β 3 β 4 WB4010 [357], prozosin [357], BRL44408 [373], silodosin, naftopidil [374], tamsulosin [361] REC15/2739 [357]; methoxamine [358], phenylephrine [358][359][360] Terazosin [360,375]…”

Section: Gsmentioning

confidence: 99%

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia

Fauss

Hudson

Grau

2022

Biology

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As the nervous system develops, nerve fibers from the brain form descending tracts that regulate the execution of motor behavior within the spinal cord, incoming sensory signals, and capacity to change (plasticity). How these fibers affect function depends upon the transmitter released, the receptor system engaged, and the pattern of neural innervation. The current review focuses upon the neurotransmitter serotonin (5-HT) and its capacity to dampen (inhibit) neural excitation. A brief review of key anatomical details, receptor types, and pharmacology is provided. The paper then considers how damage to descending serotonergic fibers contributes to pathophysiology after spinal cord injury (SCI). The loss of serotonergic fibers removes an inhibitory brake that enables plasticity and neural excitation. In this state, noxious stimulation can induce a form of over-excitation that sensitizes pain (nociceptive) circuits, a modification that can contribute to the development of chronic pain. Over time, the loss of serotonergic fibers allows prolonged motor drive (spasticity) to develop and removes a regulatory brake on autonomic function, which enables bouts of unregulated sympathetic activity (autonomic dysreflexia). Recent research has shown that the loss of descending serotonergic activity is accompanied by a shift in how the neurotransmitter GABA affects neural activity, reducing its inhibitory effect. Treatments that target the loss of inhibition could have therapeutic benefit.

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Sex differences in lower urinary tract function in mice with or without spinal cord injury

Hashimoto,

Karnup,

Daugherty

et al. 2023

Neurourology and Urodynamics

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ObjectivesWe examined sex differences of lower urinary tract function and molecular mechanisms in mice with and without spinal cord injury (SCI).MethodsSCI was induced by Th8−9 spinal cord transection in male and female mice. We evaluated cystometrograms (CMG) and electromyography (EMG) of external urethral sphincter (EUS) at 6 weeks after SCI in spinal intact (SI) and SCI mice. The mRNA levels of Piezo2 and TRPV1 were measured in L6‐S1 dorsal root ganglia (DRG). Protein levels of nerve growth factor (NGF) in the bladder mucosa was evaluated using an enzyme‐linked immunosorbent assay.ResultsSex differences were found in the EUS behavior during voiding as voiding events in female mice with or without SCI occurred during EUS relaxation periods without EUS bursting activity whereas male mice with or without SCI urinated during EUS bursting activity in EMG recordings. In both sexes, SCI decreased voiding efficiency along with increased tonic EUS activities evident as reduced EUS relaxation time in females and longer active periods of EUS bursting activity in males. mRNA levels of Piezo2 and TRPV1 of DRG in male and female SCI mice were significantly upregulated compared with SI mice. NGF in the bladder mucosa showed a significant increase in male and female SCI mice compared with SI mice. However, there were no significant differences in Piezo2 or TRPV1 levels in DRG or NGF protein levels in the bladder mucosa between male and female SCI mice.ConclusionsWe demonstrated that female and male mice voided during EUS relaxation and EUS bursting activity, respectively. Also, upregulation of TRPV1 and Piezo2 in L6‐S1 DRG and NGF in the bladder could be involved in SCI‐induced lower urinary tract dysfunction in both sexes of mice.

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Efficacy of vibegron, a novel β3‐adrenoreceptor agonist, for lower urinary tract dysfunction in mice with spinal cord injury

Cited by 9 publications

References 22 publications

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

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

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia

Sex differences in lower urinary tract function in mice with or without spinal cord injury

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