Ketamine inhibits lipopolysacharide (LPS) induced gastric luminal fluid accumulation.
ABSTRACT Lipopolysacharide (LPS) causes gastrointestinal ileus and gastric luminal fluid accumulation. Ketamine, an anti-inflammatory anesthetic agent attenuates accumulation of luminal fluid. However, its effects on gastrointestinal transit induced by endotoxemia are unknown. The purpose of this study was to determine if the anti-inflammatory properties of ketamine improve impaired gastric emptying and gastrointestinal transit because of LPS.
Rats were given ketamine (70 mg/kg i.p.) or saline 1 h before LPS (20 mg/kg, i.p.) or saline injection. Five hours after LPS injection, rats were gavaged with 1 cc consisting of 0.1 ml of 5 mm FITC Dextran added to 0.9 ml of saline. After 30 min, rats were sacrificed, and gastric emptying, gastrointestinal transit, and gastric fluid accumulation determined. Gastric and ileal mucosa were harvested for analysis of inducible nitric oxide synthase (iNOS) (Western immunoblot). Results are reported as mean +/- SE (n > or = 5 per group; ANOVA).
Ketamine did not prevent LPS induced gastrointestinal ileus, nor did it improve gastric emptying. More importantly, it did not worsen gastrointestinal function or gastric emptying when compared to saline controls. However, it did decrease LPS induced gastric luminal fluid accumulation and blunted iNOS expression in both the stomach and ileum.
These data indicate that the ability of ketamine to attenuate gastric fluid accumulation is not because of improved gastric emptying or improved gastrointestinal transit. Moreover, while iNOS may play a role in LPS induced gastric luminal fluid accumulation, it does not appear to be a major mediator of the gastrointestinal ileus caused by LPS.
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ABSTRACT: Endotoxemia from lipopolysaccharide (LPS) induces systemic cytokine production, whereas traumatic brain injury (TBI) increases intracerebral cytokine production. In anesthetic doses, ketamine has potent anti-inflammatory properties. However, its anti-inflammatory effects at subanesthetic doses and its effects on TBI-induced inflammation have not been fully investigated. We hypothesized that ketamine would attenuate both LPS- and TBI-induced inflammatory responses. Male rats received intraperitoneal (i.p.) ketamine (70 mg/kg, 7 mg/kg, or 1 mg/kg) or saline 1 hour before LPS (20 mg/kg i.p.) or saline. Five hours after LPS, rats were killed. Serum was collected for cytokine analysis. In other experiments, male rats were given ketamine (7 mg/kg i.p.) or saline 1 hour before induction of TBI with controlled cortical impact (or sham). One hour and 6 hours after injury, brain was extracted for analysis of cerebral edema and cytokine production. LPS increased the serum concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ. Ketamine dose dependently attenuated these changes. TBI caused cerebral edema and increased concentrations of cerebral IL-1α, IL-1β, IL-6, IL-10, and tumor necrosis factor-α. However, ketamine had minimal effect on TBI-induced inflammation. Although ketamine did not seem to exert any beneficial effects against TBI in the rat, it did not exacerbate cytokine production or enhance cerebral edema as some studies have suggested.The Journal of trauma 06/2011; 70(6):1471-9. DOI:10.1097/TA.0b013e31821c38bd · 2.96 Impact Factor
Article: CURRICULUM VITAE AND BIBLIOGRAPHY
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ABSTRACT: High mobility group box 1 (HMGB1) has been identified to be a critical mediator of severe sepsis. Ketamine has been shown to reduce sepsis-induced pathological complications. These effects are because of the reduced expression and release of several inflammatory mediators. However, whether ketamine affects the expression and release of HMGB1 is not known. We investigated the effect of ketamine on HMGB1 release in lipopolysaccharide (LPS)-induced macrophages in vitro and in cecal ligation and puncture (CLP)-induced septic rats in vivo, and determined its molecular mechanism of action. RAW264.7 cells or primary macrophages were incubated with or without LPS (500ng/mL) in the presence or absence of ketamine, a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580), a nuclear factor-kappa B (NF-κB) inhibitor (pyrimidine dithiocarbamate), or small interfering RNA. The protein and expression levels of inflammatory mediators, such as HMGB1, tumor necrosis factor-α, and interleukin-1β were measured using enzyme-linked immunosorbent assays and real-time polymerase chain reaction. The effect of ketamine on NF-κB and p38 MAPK activation was evaluated using enzyme-linked immunosorbent assays, Western blot analysis, and electrophoretic mobility shift assay. Western blotting was used to observe changes in translocation of HMGB1 from the nucleus to cytoplasm. In addition, CLP-induced septic rats were treated with ketamine (0.5, 5, 10mg/kg) or saline (10mL/kg) 3h after sepsis, and the levels of HMGB1 and functional parameters of multiple organs were determined using several detection kits. Seven-day survival was also assessed. Ketamine inhibited HMGB1 release in LPS-activated RAW264.7 cells and CLP-induced septic rats. Translocation of HMGB1 from the nucleus to cytosol and expression of HMGB1 mRNA were inhibited significantly by ketamine. Ketamine inhibited the translocation of NF-κB from the cytoplasm to the nucleus and phosphorylation of p38 MAPK in LPS-activated RAW264.7 cells. Rats treated with ketamine improved survival in rats and significantly reduced CLP-induced dysfunction/injury of organs. Ketamine suppresses LPS-induced HMGB1 release in LPS-activated RAW264.7 cells and a CLP-induced model of sepsis in rats by partially inhibiting NF-κB/p38 MAPK pathways. Ketamine increased survival time induced by CLP and reduced organ dysfunction in septic peritonitis.International Immunopharmacology 08/2014; DOI:10.1016/j.intimp.2014.08.003 · 2.71 Impact Factor