Hepatic effects of ketamine administration for 2 weeks in rats

Kalkan, Yıldıray; Tomak, Yakup; Altuner, Durdu; Tümkaya, Levent; Bostan, Habib; Yılmaz, Adnan; Ünal, Deniz; Kara, Adem; Turan, Alparslan

doi:10.1177/0960327112472990

Cited by 27 publications

(17 citation statements)

References 27 publications

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“…In contrast to the heart, where calcineurin and NFAT are components of an established pathway that regulates cardiac remodeling (56), little is known about the function of calcineurin/NFAT signaling in the liver (57, 58). Our study suggests that calcineurin/NFAT activation in hepatocytes induces an inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Singh

Grabner

Yanucil

et al. 2016

Kidney International

304

277

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Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature of CKD that predict poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 co-receptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Singh

Grabner

Yanucil

et al. 2016

Kidney International

304

277

View full text Add to dashboard Cite

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“…Wong et al [19] reported that ketamine abuse appeared to lead to common bile duct dilatation, microscopic bile duct injury, and even significant liver fibrosis. In a study using rat models to investigate the histological and biochemical impact of ketamine on the liver, ultrastructural changes were seen in the mitochondria and in the rough endoplasmic reticulum [20]. Furthermore, prolonged use of ketamine caused hepatocellular toxicity and histological changes in hepatocytes in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

The Risk of Upper Urinary Tract Involvement in Patients With Ketamine-Associated Uropathy

et al. 2017

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PurposeThe aims of this study were to investigate the prevalence of upper tract involvement in ketamine-associated uropathy, and to determine the predictors of hydronephrosis in patients with a history of ketamine abuse. MethodsThis was a cross-sectional study of a prospective cohort of patients with ketamine-associated uropathy. Data including demographics, pattern of ketamine abuse, pelvic pain and urgency or frequency (PUF) symptom score, uroflowmetry (UFM) parameters, serum renal function, and liver function tests were collected. Upon consultation, ultrasonography was performed to assess the function of the urinary system. ResultsFrom December 2011 to October 2015, we treated 572 patients with ketamine-associated uropathy. Of these patients, 207 (36.2%) had managed to achieve abstinence at the time of their first consultation. Ninety-six patients (16.8%) in the cohort were found to have hydronephrosis on ultrasonography. Univariate analysis identified age, duration of ketamine abuse, PUF symptom score, voided volume on UFM, serum creatinine levels >100 μmol/L, and an abnormal serum liver enzyme profile as factors associated with hydronephrosis. Logistic regression revealed the following parameters to be statistically related to hydronephrosis: age (adjusted odds ratio [OR], 1.090; 95% confidence interval [CI], 1.020–1.166; P=0.012), functional bladder capacity (adjusted OR, 0.997; 95% CI, 0.995–0.999; P=0.029), serum creatinine >100 μmol/L (adjusted OR, 3.107; 95% CI, 1.238–7.794; P=0.016, and an abnormal serum liver enzyme profile (adjusted OR, 1.967; 95% CI, 1.213–3.187; P=0.006). ConclusionsKetamine-associated uropathy can involve the upper urinary tract. Patient demographics as well as investigations of UFM, renal function tests, and liver function tests may allow us to identify at-risk patients.

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ especially with long-term use; these effects were found to result in elevated liver enzymes or caused fatty degeneration and fibrosis 8,9 . Hepatotoxicity was also significant in patients with chronic ketamine abuse, among whom bile duct dilation and symptoms of liver fibrosis have been reported 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Wai et al showed that long-term use of ketamine induced liver injury through fatty degeneration and fibrosis 9 . Prolonged administration of ketamine has also been shown to cause histopathological changes, such as sinusoidal and biliary dilation as well as mitochondrial degeneration of the liver 8,14 . Elevated serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) are additional evidence of hepatotoxicity induced by repeated ketamine administration 15 .…”

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confidence: 99%

Multimodal imaging reveals transient liver metabolic disturbance and sinusoidal circulation obstruction after a single administration of ketamine/xylazine mixture

Chen

Yang

et al. 2020

Sci Rep

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A ketamine/xylazine (K/X) mixture is widely used before and during experiments in rodents. However, the impact of short-term use of K/X mixture and its influences on data interpretation have rarely been discussed. In this study, we administered one shot of a K/X mixture and examined acute hepatic responses using biochemical analysis, histopathological examination, and non-invasive imaging to determine the delay required prior to further assessment of the liver to avoid confounding effects triggered by anaesthesia. After the K/X injection, aspartate aminotransferase (AST) in serum was significantly elevated from 3 to 48 h. Obstructed sinusoidal circulation lasting for 24 or 36 h was revealed by DCE-MRI and drug distribution analysis, respectively. Metabolic alterations were detected at 3 h by NMR analysis and FDG-PET. Moreover, ultrasonography showed that lipid droplet accumulation increased from 1 to 16 h and declined thereafter. Taken together, our findings show that the K/X mixture induces acute hepatotoxicity and metabolic disturbance, and these disturbances cause hemodynamical disorders in the liver. the required time interval for recovery from K/X impact was dependent on the chosen assay. It took at least 16 h for metabolic recovery and 36 h for recovery of sinusoidal circulation. However, the liver was not fully recovered from the injury within 48 h. Ketamine, a non-competitive antagonist to the N-methyl-D-aspartate (NMDA) receptor, is extensively applied as an adjunct anaesthetic in clinical practice and animal studies for its anaesthetic and analgesic properties, but has limited functionality in muscle relaxation 1,2. Xylazine, an alpha-2-adrenergic central nervous system agonist, serves as a supplement to ketamine; it has analgesic and sedative effects as well as muscle relaxant properties 3. Co-administered ketamine and xylazine has been shown to provide safe anaesthesia and sedation for small rodents in a dose-dependent manner 4. Although the ketamine/xylazine (K/X) combination is commonly used for anaesthesia in rodents, negative side effects can occur across different species in various types of cells, such as hepatocytes, neurons, cardiac and respiratory tissues, as well as the urinary system 5-11. These side effects are especially concerning when K/X is administered with a high dose and in cases with long-term use.

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Hepatic effects of ketamine administration for 2 weeks in rats

Cited by 27 publications

References 27 publications

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

The Risk of Upper Urinary Tract Involvement in Patients With Ketamine-Associated Uropathy

Multimodal imaging reveals transient liver metabolic disturbance and sinusoidal circulation obstruction after a single administration of ketamine/xylazine mixture

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