Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection

Sartori, Andrea; Hofer, Anna‐Sophie; Scheuber, Myriam I.; Rust, Ruslan; Kessler, Thomas M.

doi:10.1016/j.expneurol.2021.113937

Cited by 12 publications

(10 citation statements)

References 43 publications

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“…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 ). Regarding the SCI model of NDO, we found that, irrespective of the type of injury, the thoracic level was the preferred level to inflict spinal lesion, with the T8–T9 levels being particularly favored.…”

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%

“…Other SCI protocols include incomplete sectioning of the cord with a scalpel of iridectomy scissors, the most frequent of which are spinal hemisections [ 42 , 47 , 52 ]. This model is particularly useful in studies in which the goal is to compromise a particular area of the cord.…”

Section: Discussionmentioning

confidence: 99%

“…In the nervous system of NDO rats, the expression of several neuronal markers (namely CRF, GAD2, NF200, TH, VAChT, and VGLUT) was found to be generally downregulated, due to denervation associated with SCI, MMC, and PD, the latter more evident in the substancia nigra and ventral tegmental area [ 40 , 47 , 49 , 64 , 73 , 74 ]. In contrast, the expression of CGRP, a marker of sensory innervation, was upregulated in the lumbosacral spinal cord and L1 and L6 DRGs in SCI animals, in tandem with what has been described in the bladder [ 26 ] and coursing with levels of spinal NGF [ 140 ].…”

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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“…SCI can elicit morphological alterations in bladder afferent pathways, particularly in the C-fiber cell population, as well as an increase in the expression of CGRP and TRPV1 in bladder afferent neurons in rodents [9]. Two-three weeks after SCI, the density of CGRP-positive fibers in lamina 1 and 2 gradually increased to reach a level of around 50% over the original density at four weeks after SCI [10]. Neurotrophic factors such as NGF, BDNF, NT-3, and NT-4 are essential for various types of neuronal plasticity, including the emergence of LUTD in SCI [11][12][13][14].…”

Section: Ngf (Nerve Growth Factor)mentioning

confidence: 99%

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

Shimizu

Saito

Wada

et al. 2023

IJMS

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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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Acute ampakines increase voiding function and coordination in a rat model of SCI

Rana

Alom

Martinez

et al. 2023

Preprint

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Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague Dawley rats received a unilateral contusion of the T9 spinal cord (n=10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed five days post-SCI under urethane anesthesia. Data were compared to responses in spinal intact rats (n=8). The low impact ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (HPCD) was administered intravenously. The HPCD vehicle had no discernable impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

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Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection

Cited by 12 publications

References 43 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

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

Acute ampakines increase voiding function and coordination in a rat model of SCI

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