Ketamine attenuates liver injury attributed to endotoxemia: Role of cyclooxygenase-2

University of Houston, Houston, Texas, United States
Surgery (Impact Factor: 3.38). 09/2005; 138(2):134-40. DOI: 10.1016/j.surg.2005.03.024
Source: PubMed


Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury.
Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS.
LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels.
These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.

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    • "TNF-α is a macrophage-derived cytokine with chemotactic potency, which has been implicated in the acute phase reaction under various inflammatory conditions (Ming et al., 1987). The iNOS, COX-2, IL-lβ, and TNF-α genes are responsible for the damage and deleterious effects in splanchnic tissue caused as by a response to inflammatory stimuli (de Waal, 1994; Suliburk et al., 2005). "
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    ABSTRACT: Three types of resistant starch (RS) products were purchased for the evaluation of gastric injury preventive effect in Sprague-Dawley rats. We used an animal model to check for gastric injury preventive activities of these RS products in vivo. RS3 reduced the levels of serum proinflammatory cytokines of IL-6 and TNF-α as compared to those of RS2 and RS4. The gastric secretion volumes from high to low order were control rats, RS2-treated rats, RS4-treated rats, RS3-treated rats, and normal rats, whereas pH levels of gastric juice showed the opposite trend. The gastric injury level was significantly decreased by RS, demonstrating its anti-inflammatory properties, with RS3 showing the best anti-inflammatory effect. Gastric tissues of RS3 group rats showed significantly decreased mRNA and protein expression levels of inflammation-related genes of iNOS, COX-2, TNF-α, and IL-1β compared with the control group, as shown by RT-PCR and Western blot analyses. These results suggest that RS shows a gastric injury preventive effect, with RS3 showing the best inhibitory effect on gastric injury.
    Journal of the Korean Society for Applied Biological Chemistry 10/2013; 56(5). DOI:10.1007/s13765-013-3143-4 · 0.69 Impact Factor
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    • "When exposed to ketamine, hepatocytes showed an inhibition of oxidative phosphorylation (Chang et al., 2009), increased apoptotic insults (Lee et al., 2009) and reactive oxygen species (ROS) production (Reinke et al., 1998). Contrarily, ketamine also showed hepatoprotective effects which are attributed to its anti-inflammatory properties (Suliburk et al., 2005). Despite several in vitro studies (Chang et al., 2009; Lee et al., 2009; Markham et al., 1981), there is still little information on ketamine chronic effects on liver mitochondria and oxidative stress responses when in vivo models are used. "
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    ABSTRACT: Aim: Ketamine can induce hepatotoxicity which has been suggested to be dependent on mitochondrial impairment. This study investigated the long-term effects of chronic low-dose ketamine on liver mitochondrial function, oxidative stress parameters, liver histology and glycogen content. Main methods: Adult rats were administered with saline or ketamine (5 or 10mg/kg) twice a day for a fourteen-day period in order to mimic chronic treatments. Effects between groups were compared ten days after the treatment had ended. Liver mitochondrial function was monitored in isolated mitochondrial extracts through evaluation of respiration parameters and activity of respiratory complexes, as well as oxidative stress, through lipid peroxidation, protein oxidation and superoxide dismutase activity. The hepatic histology and liver glycogen content were also evaluated. Key findings: Ketamine groups showed a decreased evolution in body weight gains during the treatment period. Ketamine had no effect either on serum liver enzymes or on the oxidative stress parameters of liver mitochondria. Ketamine decreased the hepatic glycogen content, inhibited mitochondrial complex I and oxygen consumption when glutamate-malate substrate was used. Significance: These findings reflect a long-term mitochondrial bioenergetic deterioration induced by ketamine, which may explain the increased susceptibility of some patients to its prolonged or repeated use.
    Life sciences 08/2013; 93(12-14). DOI:10.1016/j.lfs.2013.08.001 · 2.70 Impact Factor
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    • "COX-2, iNOS, IL-lβ, and TNF-α genes in liver tissue could potentially be used as biomarkers for monitoring hepatic damage. Following inflammatory stimulation, both COX-2 and iNOS have been reported to induce deleterious effects in the liver [13]. Factors responsible for this hepatic response to inflammation include IL-lβ and TNF-α [12]. "
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    ABSTRACT: Bamboo salt, a Korean folk medicine, is prepared with solar salt (sea salt) and baked several times at high temperatures in a bamboo case. In this study, we compared the preventive effects of bamboo salt and purified and solar salts on hepatic damage induced by carbon tetrachloride in Sprague-Dawley rats. Compared with purified and solar salts, bamboo salts prevented hepatic damage in rats, as evidenced by significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (P < 0.05). Bamboo salt (baked 9×) triggered the greatest reduction in these enzyme levels. In addition, it also reduced the levels of the proinflammatory cytokines interleukin (IL)-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. Histopathological sections of liver tissue demonstrated the protective effect of bamboo salt, whereas sections from animals treated with the other salt groups showed a greater degree of necrosis. We also performed reverse transcription-polymerase chain reaction and western blot analyses of the inflammation-related genes iNOS, COX-2, TNF-α, and IL-1β in rat liver tissues. Bamboo salt induced a significant decrease (~80%) in mRNA and protein expression levels of COX-2, iNOS, TNF-α, and IL-1β, compared with the other salts. Thus, we found that baked bamboo salt preparations could prevent CCl4-induced hepatic damage in vivo.
    Nutrition research and practice 08/2013; 7(4):273-80. DOI:10.4162/nrp.2013.7.4.273 · 1.44 Impact Factor
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