Effects Of Ketamine And Insulin Sensitizer On Septic Mice

Sepsis with infra-abdominal infection and ensuing multiple organ dysfunction syndrome with septic shock continue to be the major cause of death in clinical settings. Septic shock involves various injury factors and complicated cell signal pathways, which has been demonstrated in both experiments and clinical trials. Neither traditional therapies, such as early fluid resuscitation, antibiotic regimens and support of metabolism, nor novel specific anti-inflammatory agents have shown positive influence on mortality due to their mono-therapeutic targets. Thus, strategies that aim to find pharmacological agents with protective effects on multiple-targets are imperative for improving survival and status in septic patients. Ketamine and insulin-sensitizer rosiglitazone are shown to have beneficial effects on many ways. Ketamine stimulates cardiovascular system, relaxes airway, inhibits neutrophils accumulation and decreases tumor necrosis factor-α (TNF-α) level in plasma; rosiglitazone promotes utilization of glucose in tissues, decreases free fatty acids levels in plasma, modulates energy metabolism and regulates expression of proinflammatory mediators by activating peroxisome proliferator activated receptors (PPARs) . At the present study, these effects are investigated on three aspects in a murine model of sepsis induced by cecal ligation and puncture (CLP) .Mortality was observed with post-treatment of KET, RSG and KR (KET combined with RSG) during 7 days after operation. The data showed a significant reduction of mortality in both KET/RSG and KR groups (P<0.05 vs. CLP group) . No statistic difference between these three groups was observed, which implied the protective mechanisms of KET and RSG may be independent.TNF-α levels in plasma at 24, 48 and 120 hour after operation were tested by ELISA. The data showed KET suppressed TNF-α level at 48h and 120h (P<0.05 vs.CLP group) , whereas no significant change was found in RSG or KR group compared with CLP group, except for an increase in KR group at 48h (P<0.05 vs. CLP group), which implied that KET, but not RSG, exerted its anti-inflammatory effects partly through decreasing TNF-α level in plasma under our experimental conditions.Pathological changes of lung, liver, kidney and small intestine were also examined under optical microscope. Degeneration and necrosis of parenchyma cells were observed in CLP group, as well as dilation, congestion, neutrophils recruitment and microthrombosis in blood vessels and interstitial swelling and inflammatory cellular infiltration. These changes were lessened in KET, RSG and KR groups.Taken together, our data demonstrated that KET and RSG decreased the mortality of septic mice and ameliorated pathological injury in several organs. KET also inhibited TNF-a level in plasma. Although KET and RSG are not the optimal drugs for septic shock, our data suggested strategies that using multiple-target and low-toxic agents to control the multiple systemic disorders in sepsis would help the treatment of septic shock and multiple organ dysfunction syndrome in clinical practice.