During sepsis, the brain may be one of the first organs affected [23, 24]. SAE, a diffuse brain dysfunction, can be detected in up to 50–70% of septic patients, and patients with acute SAE have a high mortality rate (49%) [1, 2]. Several lines of evidence indicate that an inflammatory cascade and oxidative stress injury are the main mechanisms of SAE. However, at present, the establishment of therapeutic strategies for the treatment of SAE in clinical practice is problematic.
Under septic conditions, the expression of cytokines (e.g., IL-1, IL-6, TNF-а, and IL-10) is significantly upregulated in cerebral tissues. In agreement with this, our results show that the protein concentrations of the cytokines IL-1, IL-6, and TNF-а notably increased in the cortex, hippocampus, and hypothalamus of septic rats. Numerous studies suggest that cytokines cause brain toxicity. The reported injurious effects of cytokines include nerve cell apoptosis and necrosis [6–8], neuronal bioenergetic failure and cerebral oxidative metabolism injury , axonal injury and brain tissue edema [10, 11], neurotransmitter transporter inhibition , and destruction of the blood–brain barrier .
An imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage, is termed “oxidative stress”. Oxidants are formed as a normal product of aerobic metabolism, but they can also be produced at elevated rates under pathophysiological conditions . The antioxidant systems in the body include SOD, glutathione peroxidase (GSH-Px), catalase, and GSH [26, 27]. MDA is the main oxidation product of peroxidized polyunsaturated fatty acids, and an increased MDA level is an important indication of lipid peroxidation [26, 27]. The brain is particularly susceptible to oxidative stress because of its high metabolic rate, relatively low capacity for cellular regeneration , and low antioxidant capacity due to a lack of reduced GSH [29–31]. During sepsis, oxidative stress injury is the main pathophysiological mechanism of SAE. Our experimental results showed that the levels of the antioxidants SOD and GHS notably decreased in septic rats in every region of the brain (hippocampus, hypothalamus, and cortex), whereas the MDA levels notably increased. These results are similar to previous observations that an imbalance exists between oxidants and antioxidants during sepsis.
Reactive oxygen species (ROS) including superoxide
, hydrogen peroxide (H2O2), and hydroxyl radicals are generated in both normal and pathological, biological processes. ROS system can significantly were activated and participated in the pathophysiology process of sepsis . The study found similar, in sepsis, H2O2 was increased significantly. The present study found that H2O2 significantly reduced the GPx, SOD, and CAT activities, while MDA level exposed to H2O2 was elevated,indicating disruptions of the endogenous antioxidant enzymes . Agents that inhibit the production of reactive oxygen species or increase the antioxidant defense may prevent apoptosis and protect cells from oxygen radicals damage . Insulin can prevent mitochondrial generation of H2O2 in normal rat neuronal cultures . In our results showed H2O2 were decreased in cortex, hypothalamus and hippocampus in different degree when insulin was injected by 4.8 mU · kg-1 · min-1 for 6 hours.
Above-mentioned results show that insulin can inhibit inflammatory cytokines and the oxidative stress response. The interaction between cytokines and oxidative stress has also been recently investigated. Cytokines have been reported to increase the neutrophil oxidative respiratory burst ; however, oxidative stress can be an initiator of cytokine release and cell damage . Therefore, with respect to SAE, it might be useful to inhibit the inflammatory response and correct the imbalance between oxidants and antioxidants in brain tissues. In addition to the regulation of blood glucose levels, insulin plays important roles in immune regulation and the inhibition of oxidative stress injury. Our previous studies and a number of other reports have demonstrated that insulin can significantly reduce the release of inflammatory cytokines and improve the prognosis of critically ill patients . To date, studies of insulin therapy for critical care subjects have focused on peripheral tissues, and the effects of insulin in the cerebral tissues of septic patients have not been thoroughly investigated. Therefore, in our experiment, we infused insulin intravenously at 4.8 mU · kg-1 · min-1 and maintained the blood glucose level at 140–180 mmol/dL by intravenous infusion of a 50% dextrose solution. After 6 h of insulin therapy, we found that cytokine concentrations notably decreased and oxidative stress injury in the cortex, hypothalamus, and hippocampus was alleviated in septic rats.
Serum S100B and NSE are specific biomarkers of cerebral injury [37, 38]. S100B is most abundant in glial cells of the CNS, mainly in astrocytes, while NSE is present almost exclusively in the cytoplasm of neurons (γ–γ isoenzyme) and neuroendocrine cells (α–γ isoenzyme). Therefore, in our next study, we will further examine the serum content of S100 and NSE. In the present study, we found that the serum levels of S100 and NSE were notably increased after injection of 10 mg/kg LPS. However, when insulin was injected at 4.8 mU · kg-1 · min-1 for 6 h, we found that the serum levels of S100 and NSE significantly decreased. Therefore, the results of this study indicate that insulin can inhibit cerebral injury.
In conclusion, our results show that insulin can inhibit inflammatory cytokines and the oxidative stress response and consequently improve brain tissue damage. The findings of this study may provide a basis for the development of treatment strategies for SAE in clinical practice.