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Vincristine (VCR) is one of the most widely used chemotherapy agents in treating pediatric cancer. Nonetheless, it is known to cause dose-dependent neurotoxicity which can impact virtually every organ system. Despite its widespread use, the precise impact of VCR on the lower urinary tract (LUT) remains inadequately elucidated. Our initial clinical and translational investigations suggest a sex-specific influence of childhood VCR exposure on LUT function. Thus, the current study aimed to investigate the late effects of systemic VCR exposure on LUT physiology and the underlying mechanisms, focusing on dosage and male-sex, employing juvenile CD-1 mice as a model. Male mice subjected to VCR exhibited augmented functional bladder capacity accompanied by frequent non-void contractions during awake cystometry, alongside mast cell accumulation within the bladder, compared to the saline-treated control group. Noteworthy functional changes were observed in bladder strips from the VCR group, including decreased nerve-mediated contraction, heightened contractile responses to cholinergic and purinergic agonists, enhanced responsiveness to histamine-primarily via histamine receptor 1 (Hrh1)-and an augmented relaxation effect with compound 48/80 (a mast cell degranulator), relative to the control group. Significant changes in gene expression levels associated with neuroinflammation and nociception were observed in both the bladder and lumbosacral dorsal root ganglia (Ls-DRG) of the VCR group. These findings suggest that VCR exposure during childhood, particularly in males, triggers neuroimmune responses in the bladder and Ls-DRG, amplifying responsiveness to neurotransmitters in the bladder, thereby contributing to LUT dysfunction characterized by a mixed bladder phenotype as a late effect during survivorship.
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Vejiga Urinaria , Vincristina , Animales , Masculino , Ratones , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patología , Femenino , Vincristina/efectos adversos , Vincristina/farmacología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Humanos , Factores Sexuales , Relación Dosis-Respuesta a Droga , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
The growth of antibiotic resistance to antifungal drugs contributes to the search for new ways to enhance their effectiveness and reduce toxicity. The undeniable advantage of polyene macrolide antibiotic amphotericin B (AmB) which ensures low pathogen resistance is its mechanism of action related to the formation of transmembrane pores in target lipid membranes. Here, we investigated the effects of plant flavones, chrysin, wogonin, baicalein, apigenin, scutellarein, luteolin, morin and fisetin on the pore-forming activity of AmB in the sterol-enriched membranes by electrophysiological assays. Сhrysin, wogonin, baicalein, apigenin, scutellarein, and luteolin were shown to decrease the AmB pore-forming activity in the bilayers composed of palmitoyloleylphosphocholine independently of their sterol composition. Morin and fisetin led to the increase and decrease in the AmB pore-forming activity in the ergosterol- and cholesterol-containing bilayers respectively. Differential scanning microcalorimetry of the gel-to-liquid crystalline phase transition of membrane forming lipids, molecular dynamics simulations, and absorbance spectroscopy revealed the possibility of direct interactions between AmB and some flavones in the water and/or in the lipid bilayer. The influence of these interactions on the antibiotic partitioning between aqueous solution and membrane and/or its transition between different states in the bilayer was discussed.
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Anfotericina B , Flavonas , Membrana Dobles de Lípidos , Simulación de Dinámica Molecular , Anfotericina B/farmacología , Anfotericina B/química , Flavonas/farmacología , Flavonas/química , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Antifúngicos/farmacología , Antifúngicos/química , Transición de FaseRESUMEN
Stretch-activated two-pore domain K+ (K2P) channels play important roles in many visceral organs, including the urinary bladder. The TWIK-related K+ channel TREK-1 is the predominantly expressed K2P channel in the urinary bladder of humans and rodents. Downregulation of TREK-1 channels was observed in the urinary bladder of patients with detrusor overactivity, suggesting their involvement in the pathogenesis of voiding dysfunction. This study aimed to characterize the long-term effects of TREK-1 on bladder function with global and smooth muscle-specific TREK-1 knockout (KO) mice. Bladder morphology, bladder smooth muscle (BSM) contractility, and voiding patterns were evaluated up to 12 mo of age. Both sexes were included in this study to probe the potential sex differences. Smooth muscle-specific TREK-1 KO mice were used to distinguish the effects of TREK-1 downregulation in BSM from the neural pathways involved in the control of bladder contraction and relaxation. TREK-1 KO mice developed enlarged urinary bladders (by 60.0% for males and by 45.1% for females at 6 mo; P < 0.001 compared with the age-matched control group) and had a significantly increased bladder capacity (by 137.7% at 12 mo; P < 0.0001) and compliance (by 73.4% at 12 mo; P < 0.0001). Bladder strips isolated from TREK-1 KO mice exhibited decreased contractility (peak force after KCl at 6 mo was 1.6 ± 0.7 N/g compared with 3.4 ± 2.0 N/g in the control group; P = 0.0005). The lack of TREK-1 channels exclusively in BSM did not replicate the bladder phenotype observed in TREK-1 KO mice, suggesting a strong neurogenic origin of TREK-1-related bladder dysfunction.NEW & NOTEWORTHY This study compared voiding function and bladder phenotypes in global and smooth muscle-specific TREK-1 KO mice. We found significant age-related changes in bladder contractility, suggesting that the lack of TREK-1 channel activity might contribute to age-related changes in bladder smooth muscle physiology.
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Hipertrofia , Ratones Noqueados , Contracción Muscular , Músculo Liso , Canales de Potasio de Dominio Poro en Tándem , Vejiga Urinaria , Animales , Canales de Potasio de Dominio Poro en Tándem/genética , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/deficiencia , Vejiga Urinaria/fisiopatología , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Músculo Liso/metabolismo , Músculo Liso/fisiopatología , Músculo Liso/patología , Masculino , Femenino , Envejecimiento/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores de Edad , MicciónRESUMEN
Urologic chronic pelvic pain syndrome (UCPPS) is a painful chronic condition with persistent pain originating from the pelvis that often leads to detrimental lifestyle changes in the affected patients. The syndrome develops in both sexes, with an estimated prevalence of 5.7% to 26.6% worldwide. This narrative review summarizes currently recommended therapies for UCPPS, followed by the latest animal model findings and clinical research advances in the field. The diagnosis of UCPPS by clinicians has room for improvement despite the changes in the past decade aiming to decrease the time to treatment. Therapeutic approaches targeting growth factors (i.e., nerve growth factor, vascular endothelial growth factor), amniotic bladder therapy, and stem cell treatments gain more attention as experimental treatment options for UCPPS. The development of novel diagnostic tests based on the latest advances in urinary biomarkers would be beneficial to assist with the clinical diagnosis of UCPPS. Future research directions should address the role of chronic psychologic stress and the mechanisms of pain refractory to conventional management strategies in UCPPS etiology. Testing the applicability of cognitive behavioral therapy in this cohort of UCPPS patients might be promising to increase their quality of life. The search for novel lead compounds and innovative drug delivery systems requires clinically relevant translational animal models. The role of autoimmune responses triggered by environmental factors is another promising research direction to clarify the impact of the immune system in UCPPS pathophysiology. SIGNIFICANCE STATEMENT: This minireview provides an up-to-date summary of the therapeutic approaches for UCPPS with a focus on recent advancements in the clinical diagnosis and treatments of the disease, pathophysiological mechanisms of UCPPS, signaling pathways, and molecular targets involved in pelvic nociception.
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Dolor Crónico , Dolor Pélvico , Humanos , Animales , Dolor Pélvico/terapia , Dolor Crónico/terapiaRESUMEN
The macrolide polyene antibiotic amphotericin B (AmB), remains a valuable drug to treat systemic mycoses due to its wide antifungal activity and low probability of developing resistance. The high toxicity of AmB, expressed in nephropathy and hemolysis, could be partially resolved by lowering therapeutic AmB concentration while maintaining efficacy. This work discusses the possibility of using plant polyphenols and alkaloids to enhance the pore-forming and consequently antifungal activity of AmB. We demonstrated that phloretin, phlorizin, naringenin, taxifolin, quercetin, biochanin A, genistein, resveratrol, and quinine led to an increase in the integral AmB-induced transmembrane current in the bilayers composed of palmitoyloleoylphosphocholine and ergosterol, while catechin, colchicine, and dihydrocapsaicin did not practically change the AmB activity. Cardamonin, 4'-hydroxychalcone, licochalcone A, butein, curcumin, and piperine inhibited AmB-induced transmembrane current. Absorbance spectroscopy revealed no changes in AmB membrane concentration with phloretin addition. A possible explanation of the potentiation is related to the phytochemical-produced changes in the elastic membrane properties and the decrease in the energy of formation of the lipid mouth of AmB pores, which is partially confirmed by differential scanning microcalorimetry. The possibility of AmB interaction with cholesterol in the mammalian cell membranes instead of ergosterol in fungal membranes, determines its high toxicity. The replacement of ergosterol with cholesterol in the membrane lipid composition led to a complete loss or a significant decrease in the potentiating effects of tested phytochemicals, indicating low potential toxicity of these compounds and high therapeutic potential of their combinations with the antibiotic. The discovered combinations of AmB with plant molecules that enhance its pore-forming ability in ergosterol-enriched membranes, seem to be promising for further drug development in terms of the toxicity decrease and efficacy improvement.
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PURPOSE: To investigate potential beneficial effects of tocotrienols which have been suggested to inhibit hypoxia-inducible factor (HIF) pathway, on partial bladder outlet obstruction (PBOO)-induced bladder pathology. MATERIALS AND METHODS: PBOO was surgically created in juvenile male mice. Sham-operated mice were used as controls. Animals received daily oral administration of either tocotrienols (T3) or soybean oil (SBO, vehicle) from day 0 to 13 post-surgery. Bladder function was examined in vivo by void spot assay. At 2 weeks post-surgery, the bladders were subjected to physiological evaluation of detrusor contractility in vitro using bladder strips, histology by H&E staining and collagen imaging, and gene expression analyses by quantitative PCR. RESULTS: A significant increase in the number of small voids was observed after 1 week of PBOO compared to the control groups. At 2 weeks post-surgery, PBOO+SBO mice showed a further increase in the number of small voids, which was not observed in PBOO+T3 group. PBOO-induced decrease in detrusor contractility was similar between two treatments. PBOO induced bladder hypertrophy to the same degree in both SBO and T3 treatment groups, however, fibrosis in the bladder was significantly less prominent in the T3 group than the SBO group following PBOO (1.8- vs. 3.0-fold increase in collagen content compared to the control). Enhanced levels of HIF target genes in the bladders were observed in PBOO+SBO group, but not in PBOO+T3 group compared to the control. CONCLUSIONS: Oral tocotrienol treatment reduced the progression of urinary frequency and bladder fibrosis by suppressing HIF pathways triggered by PBOO.
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Tocotrienoles , Obstrucción del Cuello de la Vejiga Urinaria , Masculino , Animales , Ratones , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria , Administración Oral , Perfilación de la Expresión GénicaRESUMEN
Multiple sclerosis (MS) often leads to the development of neurogenic lower urinary tract symptoms (LUTS). We previously characterized neurogenic bladder dysfunction in a mouse model of MS induced by a coronavirus, mouse hepatitis virus (MHV). The aim of the study was to identify genes and pathways linking neuroinflammation in the central nervous system with urinary bladder (UB) dysfunction to enhance our understanding of the mechanisms underlying LUTS in demyelinating diseases. Adult C57BL/6 male mice (N = 12) received either an intracranial injection of MHV (coronavirus-induced encephalomyelitis, CIE group), or sterile saline (control group). Spinal cord (SC) and urinary bladders (UB) were collected from CIE mice at 1 wk and 4 wks, followed by RNA isolation and NanoString nCounter Neuroinflammation assay. Transcriptome analysis of SC identified a significantly changed expression of >150 genes in CIE mice known to regulate astrocyte, microglia and oligodendrocyte functions, neuroinflammation and immune responses. Two genes were significantly upregulated (Ttr and Ms4a4a), and two were downregulated (Asb2 and Myct1) only in the UB of CIE mice. Siglec1 and Zbp1 were the only genes significantly upregulated in both tissues, suggesting a common transcriptomic link between neuroinflammation in the CNS and neurogenic changes in the UB of CIE mice.
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Infecciones por Coronavirus , Síntomas del Sistema Urinario Inferior , Esclerosis Múltiple , Vejiga Urinaria Neurogénica , Animales , Masculino , Ratones , Sistema Nervioso Central , Coronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/genética , Perfilación de la Expresión Génica , Síntomas del Sistema Urinario Inferior/genética , Ratones Endogámicos C57BL , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/genética , Esclerosis Múltiple/virología , Virus de la Hepatitis Murina/genética , Proteínas de Unión al ARN , Vejiga Urinaria , Vejiga Urinaria Neurogénica/genéticaRESUMEN
Vincristine (VCR) is one of the most common chemotherapy agents used in pediatric oncology. Despite the well-known VCR-induced peripheral neuropathy, potential impacts of VCR on lower urinary tract (LUT) function remain poorly defined. We investigated the effects of systemic VCR exposure in childhood on LUT function by using juvenile mice treated with VCR (4 mg/kg) or saline and evaluated at 5 weeks later. VCR induced a decreased urinary frequency with increased functional bladder capacity and non-void contractions. There were no changes in detrusor contractility between the groups. VCR exposure caused sexual dimorphic changes; in females, increased intravesical pressure at micturition and downregulations of a major player in bladder afferent firing, Htr3b, in the bladders, and Cav1.2 in the lumbosacral dorsal root ganglia (Ls-DRG), while male mice displayed increases in bladder compliance and detrusor activity, upregulations of IL-2, Trpa1 and Itga1 in the bladders and neuroinflammation-related genes, P2×4, P2×7, IL-2 and CD68 in the Ls-DRG. These results suggest that that systemic VCR exposure caused sensory neuropathy via sex-dimorphic mechanisms, leading to altered LUT function. These changes might clinically present as gender-specific signs or symptoms of LUT dysfunction, and follow-up urological assessment may be of benefit for pediatric cancer patients treated with VCR.
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Enfermedades del Sistema Nervioso Periférico , Vejiga Urinaria , Animales , Femenino , Humanos , Interleucina-2/efectos adversos , Masculino , Ratones , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Micción , Vincristina/efectos adversosRESUMEN
The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization in vivo in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGFA) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGFA-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGFA-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of TRPV1-Cre-ZGreen mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (i. p.) in awake animals to silence TRPV1 expressing sensory neurons in vivo during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGFA in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGFA instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGFA-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons in vivo completely reversed VEGFA-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients.
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Analgésicos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Región Lumbosacra/inervación , Percepción del Dolor/efectos de los fármacos , Dolor Pélvico/tratamiento farmacológico , Células Receptoras Sensoriales/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
BACKGROUND: Two chemotherapeutic agents used widely in pediatric oncology are vincristine (VCR) and doxorubicin (DOX), which may cause neuropathy and myopathy, respectively. The study hypothesis is that neurotoxic effects of VCR and/or myotoxic effects of DOX affect bladder physiology and manifest clinically as lower urinary tract dysfunction (LUTD). PROCEDURE: Based on a priori power analysis, 161 children divided evenly by gender were recruited. Children aged 5-10 years completed the dysfunctional voiding scoring system (DVSS) survey. The study cohort comprised cancer survivors treated with VCR and/or DOX. Healthy controls were recruited from well-child clinic visits. Exclusion criteria included pelvic-based malignancy, pelvic irradiation, pre-existing LUTD, neurologic abnormalities, and treatment with cyclophosphamide/ifosfamide. DVSS scores and presence of LUTD, defined as DVSS scores above gender-specific thresholds (males ≥9, females ≥6), were compared across cohorts. RESULTS: Median DVSS scores were higher in the study cohort (6 vs. 4, p = .003). Moreover, children in the study cohort were more likely to exceed threshold scores for LUTD (38.8% vs. 21%, p = .014; OR 1.8). Subanalysis by gender revealed female cancer survivors are more likely to report LUTD than controls (57.5% vs. 30%, p = .013, OR 1.9). This did not hold true for males (20% vs. 12.2%, p = .339). CONCLUSIONS: Childhood cancer survivors who received VCR and/or DOX reported higher rates of LUTD than controls. Female cancer survivors appear more likely to suffer from LUTD than males. Further study with a positive control cohort of cancer survivors who received non-VCR, non-DOX chemotherapy is underway to elucidate the contribution of a cancer diagnosis to LUTD.
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Supervivientes de Cáncer , Doxorrubicina , Síntomas del Sistema Urinario Inferior , Neoplasias , Vincristina , Niño , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Vejiga Urinaria , Vincristina/efectos adversosRESUMEN
OBJECTIVES: Brain-derived neurotrophic factor (BDNF) has been implicated in central neurological processes. We hypothesize that greater pain catastrophizing is associated with higher urinary BDNF levels in women with bladder pain syndrome. METHODS: A secondary analysis of a database of women with urinary urgency was conducted. We identified women who met AUA criteria of bladder pain syndrome. Urinary symptoms, pain catastrophizing, and neuropathic pain were measured using the Female Genitourinary Pain Index, Pain Catastrophizing Scale and painDETECT questionnaires respectively. The relationship of the catastrophizing score with urinary BDNF (primary outcome) and other urinary biomarkers, including nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and osteopontin, was evaluated using univariable and multivariable analyses. RESULTS: In 62 women with bladder pain syndrome, 15 (24%) reported pain catastrophizing symptoms (Pain Catastrophizing Scale score >30). Higher catastrophizing scores were associated with worse urinary symptoms, greater pelvic pain, greater neuropathic pain, and worse quality of life scores (all P < 0.01). On multivariable analysis, after controlling for age, body mass index and urinary symptoms, a higher pain catastrophizing score was associated with lower BDNF (P = 0.04) and lower VEGF levels (P = 0.03). Urinary urgency was associated with a higher NGF level (P = 0.04) while bladder pain was associated with higher levels of NGF (P = 0.03) and VEGF (P = 0.01). CONCLUSIONS: Neuroinflammatory mechanisms contribute to the central processing of pain in women with bladder pain syndrome. Worse urinary symptoms are associated with higher NGF and VEGF levels, but worse pain catastrophizing is associated with lower BDNF and VEGF levels. Urinary BDNF levels may be useful in phenotyping women who have central augmentation of pain processing.
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Catastrofización , Cistitis Intersticial , Biomarcadores , Femenino , Humanos , Factor de Crecimiento Nervioso , Calidad de Vida , Factor A de Crecimiento Endotelial VascularRESUMEN
PURPOSE OF REVIEW: Benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) is a disease complex with enormous societal burden and yet the pathogenesis of LUTS/BPH is poorly understood. We set out to review the literature on the relationship between depression, marijuana usage, and erectile dysfunction (ED) to LUTS/BPH. RECENT FINDINGS: LUTS/BPH has independent associations with depression as well as with ED. In each case, the causality and mechanistic relationship is unknown. The impact of marijuana, as it increasingly pervades the general population, on the disease complex of LUTS/BPH is not well studied but recent results support short-term benefit and long-term caution. Depression, a form of central nervous dysfunction, and ED, which is likely mediated via endothelial dysfunction, are independently associated with LUTS/BPH. The presence of cannabinoid receptors in urologic organs, coupled with recent population studies, supports a modulatory effect of marijuana on voiding although an enormous knowledge gap remains.
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Depresión , Disfunción Eréctil , Síntomas del Sistema Urinario Inferior , Fumar Marihuana , Hiperplasia Prostática , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/fisiopatología , Depresión/fisiopatología , Depresión/psicología , Disfunción Eréctil/etiología , Disfunción Eréctil/psicología , Disfunción Eréctil/terapia , Humanos , Síntomas del Sistema Urinario Inferior/etiología , Síntomas del Sistema Urinario Inferior/psicología , Síntomas del Sistema Urinario Inferior/terapia , Masculino , Fumar Marihuana/efectos adversos , Fumar Marihuana/fisiopatología , Fumar Marihuana/psicología , Fumar Marihuana/terapia , Hiperplasia Prostática/etiología , Hiperplasia Prostática/psicología , Hiperplasia Prostática/terapia , Factores de TiempoRESUMEN
Bladder and bowel dysfunction (BBD) is a common yet underdiagnosed paediatric entity that describes lower urinary tract symptoms (LUTS) accompanied by abnormal bowel patterns manifested as constipation and/or encopresis. LUTS usually manifest as urgency, urinary frequency, incontinence, and urinary tract infections (UTI). Despite increasing recognition of BBD as a risk factor for long-term urinary tract problems including recurrent UTI, vesicoureteral reflux, and renal scarring, the mechanisms underlying BBD have been unclear, and treatment remains empirical. We investigated how constipation affects the lower urinary tract function using a juvenile murine model of functional constipation. Following four days of functional constipation, animals developed LUTS including urinary frequency and detrusor overactivity evaluated by awake cystometry. Physiological examination of detrusor function in vitro using isolated bladder strips, demonstrated a significant increase in spontaneous contractions without affecting contractile force in response to electrical field stimulation, carbachol, and KCl. A significant upregulation of serotonin receptors, Htr2a and Htr2c, was observed in the bladders from mice with constipation, paralleled with augmented spontaneous contractions after pre-incubation of the bladder strips with 0.5 µM of serotonin. These results suggest that constipation induced detrusor overactivity and increased excitatory serotonin receptor activation in the urinary bladder, which contributes to the development of BBD.
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Canales de Calcio/metabolismo , Estreñimiento/complicaciones , Receptor de Serotonina 5-HT2A/metabolismo , Transducción de Señal , Canales Catiónicos TRPV/metabolismo , Vejiga Urinaria Hiperactiva/etiología , Vejiga Urinaria/fisiopatología , Animales , Estreñimiento/metabolismo , Estreñimiento/fisiopatología , Masculino , Ratones Endogámicos C57BL , Vejiga Urinaria/metabolismo , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/fisiopatologíaRESUMEN
PURPOSE: The pathogenesis of bladder pain is poorly understood. Our hypothesis is that in women with urinary urgency without incontinence, bladder pain is associated with the presence of neurogenic inflammation in the bladder wall and neuroinflammatory biomarkers in the urine. METHODS: We conducted a prospective cross-sectional study of women with urinary urgency without incontinence. Urinary symptoms were measured using Female Genitourinary Pain Index. Neuropathic pain, a clinical biomarker of neuroinflammation, was measured using the PainDETECT questionnaire. Inflammatory neuropeptides measured in the urine included nerve growth factor (NGF), brain-derived neurotrophic factor, vascular endothelial growth factor, and osteopontin. Neuropathic pain scores and urinary neuropeptide levels were compared between patients with and without bladder pain using univariable and multivariable analyses. RESULTS: In 101 women with urinary urgency without incontinence, 62 (61%) were in the bladder pain group (visual analog scale score, ≤ 3), whereas 39 (39%) were in the no bladder pain group. Urinary symptom scores (5.0 ± 3.1 versus 3.5 ± 2.4, P < 0.001) and neuropathic pain scores (13.3 ± 8.6 vs 5.1 ± 4.8, P < 0.001) were significantly higher for the bladder pain group than for the no bladder pain group. On multivariable analysis after controlling for age, body mass index, and severity of urinary urgency, bladder pain score was significantly associated with elevated urinary levels of vascular endothelial growth factor (P = 0.04) and osteopontin (P = 0.02), whereas the neuropathic pain score was significantly associated with an increased NGF level (P = 0.03). CONCLUSIONS: In women with urinary urgency without incontinence, bladder pain is associated with the presence of clinical and urinary biomarkers of neuroinflammation.
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Cistitis Intersticial/diagnóstico , Enfermedades Neuroinflamatorias/diagnóstico , Adulto , Biomarcadores/orina , Factor Neurotrófico Derivado del Encéfalo/orina , Estudios Transversales , Cistitis Intersticial/orina , Femenino , Humanos , Persona de Mediana Edad , Factor de Crecimiento Nervioso/orina , Enfermedades Neuroinflamatorias/orina , Osteopontina/orina , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Factor A de Crecimiento Endotelial Vascular/orina , Escala Visual AnalógicaRESUMEN
Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11/fisiología , Hiperalgesia/prevención & control , Inflamación/fisiopatología , Neuroglía/enzimología , Nocicepción/fisiología , Receptor de Adenosina A1/fisiología , Receptor Muscarínico M3/fisiología , Animales , Bencilatos/farmacología , Clozapina/análogos & derivados , Clozapina/farmacología , Adyuvante de Freund/toxicidad , Genes Sintéticos , Calor , Hiperalgesia/fisiopatología , Inflamación/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Agonistas Muscarínicos/farmacología , Neuroglía/fisiología , Nortropanos/farmacología , Regiones Promotoras Genéticas , Agonistas del Receptor Purinérgico P1/farmacología , Antagonistas de Receptores Purinérgicos P1/farmacología , Receptor de Adenosina A1/efectos de los fármacos , Receptor Muscarínico M3/efectos de los fármacos , Receptor Muscarínico M3/genética , Receptores Acoplados a Proteínas G , Proteínas Recombinantes de Fusión/efectos de los fármacos , Proteínas Recombinantes de Fusión/metabolismo , Teofilina/análogos & derivados , Teofilina/farmacología , Tacto , Xantinas/farmacologíaRESUMEN
AIMS: Multiple sclerosis (MS) is characterized by demyelinated white matter plaque throughout the central nervous system. Plaque involvement in regions that regulate micturition may be associated with urinary symptom severity in patients with MS. The aim of this prospective study is to investigate the relationship between cerebral plaque volume (PV), location, and urinary symptoms in women with MS. METHODS: We conducted a case-control pilot study of women with MS undergoing routine yearly brain MRI. Women were administered the American Urologic Association-Symptom Index (AUA-SI) and divided into two groups: severe urinary symptoms (AUA-SI ≥20) and mild symptoms (AUA-SI ≤7). PV and location in the brain were determined using a validated automated white matter lesion segmentation algorithm. RESULTS: This study of 36 women found that the median total PV did not differ between groups. Women with severe urinary symptoms had larger median PV in the left frontal lobe (LFL) and right limbic lobe (RLL) compared with women with mild urinary symptoms. Within the RLL, women with severe symptoms had a larger median PV in the right cingulate gyrus (RCG). There was a moderate correlation between LFL lesion volume and RLL lesion volume with the AUA emptying subscore; however, these regions did not correlate with the storage subscore. CONCLUSIONS: This preliminary study found urinary symptom severity in women with MS is associated with PV in the RCG and LFL, and not total cerebral PV. These findings may explain why disease burden alone is not a predictor of severity or type of voiding dysfunction in patients with MS.
Asunto(s)
Encéfalo/diagnóstico por imagen , Síntomas del Sistema Urinario Inferior/diagnóstico por imagen , Esclerosis Múltiple/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Síntomas del Sistema Urinario Inferior/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Proyectos Piloto , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Micción/fisiologíaRESUMEN
Patients with multiple sclerosis (MS) develop a variety of lower urinary tract symptoms (LUTS). We previously characterized a murine model of neurogenic bladder dysfunction induced by a neurotropic strain of a coronavirus. In the present study, we further study the role of long-lasting neurodegeneration on the development of neurogenic bladder dysfunction in mice with corona-virus induced encephalitis (CIE). Long-term follow up study revealed three phenotypes of neurodegenerative symptom development: recovery (REC group), chronic progression (C-PRO group) and chronic disease with relapsing-remitting episodes (C-RELAP group). The levels of IL-1ß in REC group, IL-10 in C-RELAP group, and IL-1ß, IL-6, IL-10 and TNF-α in C-PRO group were diminished in the brain. The levels of TNF-α in REC group and INF-γ, IL-2, TGF-ß and TNF-α in the C-PRO group were also diminished in the urinary bladder. Mice in C-RELAP group showed a delayed recovery of voiding function. In vitro contractility studies determined a decreased basal detrusor tone and reduced amplitude of nerve-mediated contractions in C-RELAP group, whereas C-PRO group had elevated muscle-mediated contractions. In conclusion, mice with CIE developed three phenotypes of neurologic impairment mimicking different types of MS progression in humans and showed differential mechanisms driving neurogenic bladder dysfunction.