Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamine-injected mice

Shen, Cheng‐Huang; Wang, Shou-Tsung; Lee, Ying‐Ray; Liu, Shiau‐Yuan; Li, Yi‐Zhen; Wu, Jiann-Der; Chen, Yu‐Ju; Liu, Yi‐Wen

doi:10.3892/mmr.2014.2823

Cited by 28 publications

(29 citation statements)

References 24 publications

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“…In our study, the dose of 30 mg·kg Ϫ1 ·day Ϫ1 has been previously shown to induce mouse ketamine cystitis (24). This dose did induce voiding dysfunction, as shown in this and another study (22), yet a higher ketamine concentration and/or longer exposure time might be needed to induce more severe lower urinary tract damage, like hematuria and hydronephrosis, in mice. It has been reported in a rat model that 50 mg·kg Ϫ1 ·day Ϫ1 ketamine injection induced hematuria at a 16-wk time point (8).…”

Section: Ketamine D Ketaminesupporting

confidence: 72%

“…Recent reports have indicated that ketamine-treated rats exhibit increased expression of occludin and decreased expression of cadherin and the tight junction protein zonula occludens (ZO)-1, suggesting a defect in the urothelial barrier (8,18). Changes in keratin family genes were also observed in urothelia of ketamine-treated mice (22). Moreover, inflammatory molecules such as cyclooxygenase-2 and apoptotic signals were observed in urothelia, confirming the urothelial pathology in ketamine cystitis (10,17).…”

mentioning

confidence: 82%

“…5-9). The urothelial barrier plays crucial roles in normal bladder function, and recent rat models reported ketamine-impaired urothelial barrier with urothelial inflammation and apoptosis (10,14,18,22,24). Intriguingly, only ϳ50% of human ketamine cystitis patients have denuded urothelial mucosa and ulceration (17).…”

Section: Ketamine D Ketaminementioning

confidence: 99%

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Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Rajandram¹,

Ong

Razack

et al. 2016

American Journal of Physiology-Renal Physiology

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Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg(-1)·day(-1) ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis.

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Section: Ketamine D Ketaminesupporting

confidence: 72%

mentioning

confidence: 82%

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Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Rajandram¹,

Ong

Razack

et al. 2016

American Journal of Physiology-Renal Physiology

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“…In fact, some authors have found in animal models evidence of increased permeability of the urothelium exposed to ketamine and this could explain the damage beyond the superficial layer. [13][14][15] As previously mentioned, the presence of apoptotic-like bodies in the monolayer experiments led us to suppose that apoptosis may play a role in the observed growth decline. The presence of apoptosis within the urothelium in patients with KIC has already been observed.…”

Section: Discussionmentioning

confidence: 61%

Demonstration of the direct impact of ketamine on urothelium using a tissue engineered bladder model

Bureau

Pelletier

Rousseau

et al. 2015

CUAJ

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Introduction: Ketamine is a common recreational drug. Severe lower urinary tract symptoms associated with its consumption have been reported, but little is known about the involved mechanisms. The effect of ketamine, which is excreted in urine, was evaluated by its application on an in vitro three-dimensional human tissue-engineered bladder model composed of an urothelium and a submucosa. Methods: Human urothelial cells were cultured with medium containing various concentrations of ketamine and harvested at different times to obtain growth curves. Using this model, specific activity of caspase-3 was measured to assess the level of apoptosis induced by ketamine. Finally, a human tissue-engineered bladder model was used. Urothelial cells were plated on a stromal layer made of dermal fibroblasts and incubated at the air/liquid interface to allow their differentiation. Ketamine was then put on the mature urothelium using paper or agarose vectors for 48 hours. Results: The presence of ketamine increased cells' doubling times from 1.26 days for control to 1.38 days (p = 0.14) and 1.78 days (p < 0.01) for the 0.5 mM and 1.5 mM concentrations, respectively. 5 mM and 10 mM of ketamine led to decline in the major cell population. Exposure to 5 mM ketamine induced apoptosis, confirmed by a 2.5-fold increase in capase-3 specific activity from control (p = 0.03). The structure and cellular cohesion of the urothelium on the three-dimensional model, especially in the intermediate layers, were severely affected in a concentration dependant fashion with both vectors. Conclusion:The presence of ketamine in the bladder directly damages the urothelium through the induction of apoptosis.

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“…Baker et al showed that ketamine‐induced toxicity to urothelial cells by high and sustained intracellular calcium ion concentration, which ultimately led to apoptosis 40 . This damage acts in a dose and time‐dependent manner, stimulating mitochondrial‐dependent and endoplasmic reticulum stress apoptosis and autophagy 41,43‐46 . Chuang et al showed that ketamine and norketamine levels were much higher in the 28‐day treated group compared to the 14‐day group.…”

Section: Evidencementioning

confidence: 99%

What urologists need to know about ketamine‐induced uropathy: A systematic review

Castellani

Pirola

Gubbiotti

et al. 2020

Neurourology and Urodynamics

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Aims: Ketamine is a general anesthetic. Dissociative effects and low cost led ketamine becoming an illegal recreational drug in young adults. Ketamineinduced uropathy (KIU) is one of the complications observed in abusers. This study aimed to provide a systematic literature review on KIU clinical presentation, pathophysiology, and treatments. Methods: We performed the literature search in PubMed, Web of Science, Scopus, and Embase using the terms ketamine and bladder. English papers on human and animal studies were accepted. Results: A total of 75 papers were selected. Regular ketamine users complain about severe storage symptoms and pelvic pain. Hydronephrosis may develop in long-term abusers and is correlated to the contracted bladder, ureteral stenosis, or vesicoureteral reflux due to ureteral involvement and/or bladder fibrosis. Cystoscopy shows ulcerative cystitis. Ketamine in urine might exert direct toxicity to the urothelium, disrupting its barrier function and enhancing cell apoptosis. The presence of ketamine/ions in the bladder wall result in neurogenic/IgE-mediated inflammation, stimulation of the inducible nitric oxide synthase-cytokines-cyclooxygenase pathway with persistent inflammation and fibrosis. Abstinence is the first therapeutic step. Anti-inflammatory drugs, analgesics and anticholinergics, intravesical instillation of hyaluronic acid, hydrodistension and intravesical injection of botulin toxin-A were helpful in patients with early-stage KIU. In patients with end-stage disease, the control of intractable symptoms and the increase of bladder capacity were the main recommendations to perform augmentation enterocystoplasty.Conclusions: KIU is becoming a worldwide health concern, which should be taken into account in the differential diagnosis of ulcerative cystitis. K E Y W O R D S cystitis, inflammation, ketamine, lower urinary tract symptoms, substance-related disorders, urinary tract 1050 | CASTELLANI ET AL.

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Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamine-injected mice

Cited by 28 publications

References 24 publications

Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Demonstration of the direct impact of ketamine on urothelium using a tissue engineered bladder model

What urologists need to know about ketamine‐induced uropathy: A systematic review

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