[The nonlinear relationship between the resuscitation therapy and intensive insulin therapy in severe sepsis and septic shock patients].

OBJECTIVE: To study the relationship between the resuscitation therapy and intensive insulin therapy on stress-induced hyperglycemia in severe sepsis and septic shock patients, and to evaluate the value on nonlinear viewpoint in the treatment of patients with sepsis. METHODS: The data of 129 hospitalized patients with severe sepsis and septic shock were analyzed and they were divided into eight groups every 6 hours in ascending order for full recovery. The resuscitation therapy time of each group was compared with insulin dosage in each unit time with nonlinear least square method. RESULTS: The relationship of the exponential function fit very well between the resuscitation therapy time of each group and the insulin dosage in each unit time. The exponential curve equation was y=e0.739 3-0.015 2x2 (a=0.739 3, b=0.015 2) and the curve fit very well (R2=0.976 943 6). CONCLUSION: It conforms to the nonlinear viewpoint that the resuscitation therapy time is closely correlated with recovery of dysfunction of endocrine system during the treatment for patients with severe sepsis and septic shock. Therefore, the essence of successful treatment is to concentrate on helping the body rebuild the disorganized network and the recovery of physiological harmony rather than to support and repair the damaged organs.

Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury.

Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 µg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis.

3-methyladenine, an autophagic inhibitor, attenuates therapeutic effects of sirolimus on scopolamine-induced cognitive dysfunction in a rat model.

Previous studies have demonstrated that sirolimus has therapeutic effects for Alzheimer's disease which characterized by cognitive dysfunction. However, its underlying mechanisms have not been fully elucidated. In the present study, we aimed to investigate the mechanisms of therapeutic effects of sirolimus for cognitive dysfunction rat model which induced by chronic administration of scopolamine. Forty Wistar rats were randomly divided into 4 groups (n=10 each): saline group and scopolamine group, sirolimus plus scopolamine group and 3-methyladenine pretreatment group. Morris water maze test was applied to measure the cognitive function of rat. After behavioral test, rats were sacrificed and prefrontal cortex and hippocampus were harvested for measuring amyloid-ß (Aß), Beclin-1 and mammalian target of rapamycin (mTOR). Compared with saline group, scopolamine administered significantly decreased the cognitive performance of rats during the Morris water maze test and changed Aß, Beclin-1 and mTOR levels in rat prefrontal cortex and hippocampus (P<0.05); In addition, rats in sirolimus plus scopolamine group significantly reversed scopolamine-induced effects (P<0.05). Most importantly, 3-methyladenine abrogated the effects of sirolimus on scopolamine-induced cognitive dysfunction (P<0.05). In conclusion, the mechanism of sirolimus exerting therapeutic effects for scopolamine-induced cognitive dysfunction is likely related to the activation of autophagy.

Chronic lipopolysaccharide exposure induces cognitive dysfunction without affecting BDNF expression in the rat hippocampus.

Previous studies have shown that lipopolysaccharide (LPS) has the potential to cause cognitive dysfunction. However, the underlying pathogenesis has yet to be fully elucidated. Increasing attention is being focused on infection in the central nervous system. Therefore, the present study aimed to investigate the behavioral performance of rats receiving intraperitoneal injections of LPS and to determine the expression levels of amyloid-ß (Aß), brain-derived neurotrophic factor (BDNF) and pro-inflammatory cytokines in the hippocampus. In total, 30 male Wistar rats were randomly divided into 3 groups (each n=10): Control and 3 and 7 day LPS administration groups. The rats were intraperitoneally injected with saline or LPS for 3 or 7 days. Following this, rats performed the Morris water maze test, in which the latency to the platform and proportion of time spent in the target quadrant were recorded. Rats were then sacrificed and the hippocampi were harvested for determination of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), Aß and BDNF expression levels. LPS administration for 3 and 7 days significantly increased the latency to the platform and decreased the proportion of time spent in the target quadrant compared with those in the control group, (P<0.05). Administration of LPS for 3 and 7 days induced statistically significant increases in the expression levels of IL-1ß, IL-6 and TNF-α in the hippocampus, compared with those in the control group (P<0.05). Additionally, the administration of LPS for 7 days induced a statistically significant increase in the expression level of Aß in the hippocampus, compared with that in the control group (P<0.05). However, the administration of LPS did not elicit a statistically significant change in the expression level of BDNF in the hippocampus, compared with that in the control group (P>0.05). The results indicate that LPS induces cognitive dysfunction, which is associated with increased expression levels of pro-inflammatory cytokines and Aß, but does not affect the expression of BDNF in the hippocampus.

Effects of BD1047, a σ1 receptor antagonist, on the expression of mTOR, Camk2γ and GSK-3ß in fluvoxamine-treated N2a cells.

Fluvoxamine, a common antidepressant agent, is designed to exert its pharmacological effect by inhibiting synaptic serotonin reuptake. However, increasing evidence has demonstrated that σ1 receptors are likely to be involved in the mechanism of action of fluvoxamine. The present study aimed to observe the effects of fluvoxamine on the expression levels of mammalian target of rapamycin (mTOR), Ca2+/calmodulin-dependent protein kinase 2γ (Camk2γ) and glycogen synthase kinase-3ß (GSK-3ß) in fluvoxamine-treated N2a cells and attempted to elucidate whether σ1 receptors mediate the pharmacological effects of fluvoxamine. The N2a cells were randomly divided into three groups (each n=6): DMEM group (D group), 0.5 µmol/l fluvoxamine group (F group) and 0.2 µmol/l BD1047 (a σ1 receptor antagonist) + 0.5 µmol/l fluvoxamine group (BF group). Western blotting was used to determine the expression levels of mTOR, Camk2γ and GSK-3ß in the cultured N2a cells after two days of incubation. The F group exhibited significant increases in the expression levels of mTOR and Camk2γ and a significant reduction in the expression levels of GSK-3ß compared with those in the D group (P<0.01). By contrast, the BF group demonstrated significant reductions in the expression levels of mTOR and Camk2γ and a significant increase in the expression levels of GSK-3ß, compared with those in the F group (P<0.01). These results suggest that σ1 receptors mediate fluvoxamine-elicited changes in the expression levels of mTOR, Camk2γ and GSK-3ß in N2a cells, which indicates that σ1 receptors are likely to be involved in the pharmacological effects of fluvoxamine.

Ketamine attenuates the lipopolysaccharide-induced inflammatory response in cultured N2a cells.

The use of ketamine is recommended in patients with sepsis undergoing surgery due to its anti-inflammatory effects. However, a paucity of data exists with regard to the anti-inflammatory effects of ketamine in the central nervous system. Therefore, the present study aimed to investigate the effect of ketamine on lipopolysaccharide (LPS)­induced inflammatory responses in cultured Neuro2a (N2a) cells and to elucidate its potential mechanism of action. N2a cells were randomly divided into the following 3 groups (n=6): The DMEM culture solution administration alone group, the 0.5 µmol/l LPS administration alone group and the 1 µmol/l ketamine plus 0.5 µmol/l LPS administration group. The expression levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB and inducible nitric oxide synthase (iNOS) were determined. LPS-treated N2a cells exhibited a significant increase in the expression levels of IL-1ß, IL-6, TNF-α, NF-κB and iNOS, while the administration of ketamine eliminated the LPS-induced production of IL-1ß, IL-6, TNF-α, NF-κB and iNOS. Based on our data, we hypothesized that the anti-inflammatory effect exerted by ketamine on N2a cells was potentially due to the inhibition of NF-κB and iNOS.