Methyl-beta-cyclodextrin and myriocin alleviate blood–brain barrier impairment in septic rats

To evaluate the effect of sleep deprivation on cognitive function in septic rats and its relationship with neuronal glycolysis isoenzyme phosphofructokinase-2/fructose-2, 6-diphosphatase 3 (PFKFB3). Fifty-six healthy male Sprague-Dawley (SD) rats were randomly divided into 4 groups (n = 14): control group (Con group), sepsis group (LPS group), sepsis+sleep deprivation group (LPS+SD group), sepsis+sleep deprivation+glycolysis inhibitor 3-PO treatment group (LPS+SD+3-PO group). The sepsis model was established by intraperitoneal injection of lipopolysaccharide (LPS) 10 mg/kg. Rats in LPS+SD group were treated with sleep deprivation using a sleep deprivation instrument 24 hours after LPS injection. The LPS+SD+3-PO group was intraperitoneally injected with LPS for 24 hours, and then injected with 3-PO 50 mg/kg, followed by sleep deprivation. Novel object recognition experiments were performed 72 hours after LPS injection. Subsequently, blood and brain tissue samples were collected. The contents of lactate (Lac), reactive oxygen species (ROS) and serum tumor necrosis factor-α (TNF-α), neuron-specific enolase (NSE), pyruvate in brain tissue were detected by enzyme-linked immunosorbent assay (ELISA). Then, the lactate/pyruvate ratio was calculated. Na+-K+-ATPase activity in brain tissue was detected by colorimetry. Morphological changes in hippocampus were detected by hematoxylin-eosin (HE) staining. And the protein expression levels of PFKFB3, ZO-1 and cleaved caspase-3 were measured by Western blotting. Compared with Con group, the novel object recognition index of LPS group was decreased, the levels of NSE, TNF-α, lactate/pyruvate ratio in serum and the levels of Lac, ROS and dry-wet weight ratio in brain tissue were significantly increased, Na+-K+-ATPase activity in brain tissue was decreased, the protein expressions of PFKFB3, caspase-3 were up-regulated, ZO-1 expression was down-regulated, and the neurons in hippocampus were slightly degenerated. Compared with LPS group, the novel object recognition index of LPS+SD group was further decreased [(39.4±5.3)% vs. (54.5±7.6)%)], serum NSE, TNF-α, lactate/pyruvate ratio and brain tissue Lac, ROS, dry-wet weight ratio were further increased [NSE (μg/L): 3.21±0.42 vs. 2.55±0.36, TNF-α (ng/L): 139.4±19.7 vs. 92.2±13.5, lactate/pyruvate ratio: 29.7±5.5 vs. 19.2±4.2, Lac (μmol/g): 19.51±2.33 vs. 11.34±1.52, ROS (kU/g): 117.4±18.7 vs. 78.2±11.8, dry-wet weight ratio: (81.3±9.2)% vs. (64.3±6.6)%], and Na+-K+-ATPase activity was further decreased (mmol×L-1×h-1: 1.88±0.34 vs. 2.91±0.39), the protein expressions of PFKFB3, caspase-3 were further up-regulated and ZO-1 expression was further down-regulated (PFKFB3/β-actin: 0.80±0.11 vs. 0.45±0.07, caspase-3/β-actin: 0.71±0.09 vs. 0.37±0.05, ZO-1/β-actin: 0.31±0.05 vs. 0.61±0.08). The differences were statistically significant (all P < 0.05). HE staining showed that the degeneration of neurons in hippocampus was significantly aggravated. Compared with LPS+SD group, the novel object recognition index of LPS+SD+3-PO group was increased [(50.8±5.9)% vs. (39.4±5.3)%], NSE, TNF-α, lactate/pyruvate ratio of serum and Lac, ROS, dry-wet weight ratio of brain tissue were significantly decreased [NSE (μg/L): 2.60±0.33 vs. 3.21±0.42, TNF-α (ng/L): 103.7±18.3 vs. 139.4±19.7, lactate/pyruvate ratio: 17.4±5.1 vs. 29.7±5.5, Lac (μmol/g): 13.68±2.02 vs. 19.51±2.33, ROS (kU/g): 86.9±14.5 vs. 117.4±18.7, dry-wet weight ratio: (67.7±6.9)% vs. (81.3±9.2)%], and Na+-K+-ATPase activity was increased (mmol×L-1×h-1: 2.82±0.44 vs. 1.88±0.34). The protein expressions of PFKFB3, caspase-3 were down-regulated and ZO-1 expression was up-regulated (PFKFB3/β-actin: 0.50±0.06 vs. 0.80±0.11, caspase-3/β-actin: 0.43±0.06 vs. 0.71±0.09, ZO-1/β-actin: 0.52±0.06 vs. 0.31±0.05). The differences were statistically significant (all P < 0.05). HE staining showed that the degeneration of neurons in hippocampus was significantly improved. Sleep deprivation could aggravate neuroinflammation, neuronal degeneration and apoptosis in septic rats, resulting in destruction of blood-brain barrier and cognitive impairment. 3-PO treatment significantly alleviate the injury and degeneration of hippocampal neurons in septic rats, inhibit neuroinflammation and apoptosis, and improve cognitive dysfunction, which may be related to the inhibition of glycolytic isoenzyme PFKFB3.

BackgroundBlood-brain barrier (BBB) impairment plays a significant role in the pathogenesis of sepsis-associated encephalopathy (SAE). However, the molecular mechanisms are poorly understood. In the present study, we aimed to investigate the regulatory relationship between the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, microRNA (miR)-181b and its target genes in sepsis in vivo and in vitro.MethodsFour rat models (sham, sepsis, sepsis plus STAT3 inhibitor (Stattic), and sepsis plus miR-181b inhibitor [sepsis + anta-miR-181b]) were established. For the in vitro experiments, rat brain microvascular endothelial cells (rBMECs) and rat brain astrocytes (rAstrocytes) were cultured with 10% serum harvested from sham, sepsis, and sepsis + anta-miR-181b rats. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-QPCR) analysis was carried out to detect the binding and enrichment of the JAK/STAT3 signal core transcription complex in the miR-181b promoter region. Dual-luciferase reporter gene assay was conducted to test miR-181b and its target genes. The cell adhesion rate of rBMECs was also measured.ResultsDuring our investigations, the expression levels of miR-181b, p-JAK2, p-STAT3, and C/EBPβ were found to be significantly increased in the septic rats compared with the sham rats. STAT3 inhibitor halted BBB damage by downregulating the expression of miR-181b. In addition, miR-181b targeted sphingosine-1-phosphate receptor 1 (S1PR1) and neurocalcin delta (NCALD). The up-regulated miR-181b significantly decreased the cell adhesion rate of rBMECs. The administration of miR-181b inhibitor reduced damage to the BBB through increasing the expression of S1PR1 and NCALD, which again proved that miR-181b negatively regulates SIPR1 and NCALD to induce BBB damage.ConclusionsOur study demonstrated that JAK2/STAT3 signaling pathway induced expression of miR-181b, which promoted BBB impairment in rats with sepsis by downregulating S1PR1 and decreasing BBB cell adhesion. These findings strongly suggest JAK2/STAT3/miR-181b axis as therapeutic target in protecting against sepsis-induced BBB damage.

The effects of immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M on blood-brain barrier integrity and survival rates in septic rats were comparatively investigated. Sepsis was induced by cecal ligation and perforation in Sprague-Dawley rats. The animals were divided into the following groups: Sham, cecal ligation and perforation, cecal ligation and perforation plus immunoglobulin G (250 mg/kg, intravenous), and cecal ligation and perforation plus immunoglobulins enriched with immunoglobulin A and immunoglobulin M (250 mg/kg, intravenous). Immunoglobulins were administered 5 mins before cecal ligation and perforation and the animals were observed for behavioral changes for 24 hrs following cecal ligation and perforation. Blood-brain barrier permeability was functionally and structurally evaluated by determining the extravasation of Evans Blue and horseradish peroxidase tracers, respectively. Immunohistochemistry and Western blotting for occludin were performed. The high mortality rate (34%) noted in the septic rats was decreased to 15% and 3% by immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M, respectively (p < .01). Both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M alleviated the symptoms of sickness behavior in the septic rats, with the animals becoming healthy and active. Increased extravasation of Evans Blue into the brain tissue of the septic rats was markedly decreased with the administration of both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M (p < .01). Occludin expression remained essentially unchanged in all groups, including the cecal ligation and perforation group. In the cecal ligation and perforation group, increased luminal and abluminal vesicles containing electron-dense horseradish peroxidase-reaction product were noted in the cytoplasm of endothelial cells located in the hippocampus and the cerebral cortex. Tight junction was ultrastructurally intact, suggesting that the transcellular pathway is responsible for the blood-brain barrier breakdown in sepsis. Following immunoglobulin G or immunoglobulins enriched with immunoglobulin A and immunoglobulin M treatment, no ultrastructural evidence of leaky capillaries in the brain was observed in the septic rats, indicating the blockade of the transcellular pathway by immunoglobulins administration. Our study suggests that immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M improve the integrity of the blood-brain barrier and inhibits cecal ligation and perforation-induced symptoms of sickness behavior in rats.

To evaluate the effects of noise, bright light and mechanical stimulation on sleep, blood-brain barrier and cognitive function in septic rats. Forty male Sprague-Dawley (SD) rats were selected and intraperitoneal injection of 10 mg/kg lipopolysaccharide (LPS) was used to establish sepsis model. 0, 30, 45, 60, 75 dB noise stimulation or 0, 50, 100, 200, 400 Lux light stimulation were given to rats (all n = 4). The serum levels of cortisol and melatonin, and the cerebral content of Evans blue (EB) were measured 96 hours after the stimulation to determine the optimal intensity of intervention. The other 40 SD rats were randomly divided into control group (Con group), LPS group, noise intervention group (LPS+60 dB group), 200 Lux light intervention group (LPS+200 Lux group) and mechanical stimulation group (LPS+MS group), with 8 rats in each group. The open fields test and fear conditioning test were used to evaluate the exploratory behavior and cognitive function 96 hours after corresponding stimulation. The enzyme linked immunosorbent assay (ELISA) was used to detect cerebral level of interleukin-6 (IL-6) and serum levels of cortisol and melatonin. The blood-brain barrier integrity was assessed by EB staining. The protein levels of ZO-1, Claudin-5 and caspase-3 in the hippocampus were detected by Western blotting to assess the blood-brain barrier integrity and neuronal apoptosis. Compared with 0 dB group or 0 Lux group, the serum melatonin concentration in 60 dB group and 200 Lux group were significantly reduced, while the serum cortisol concentration and cerebral EB content were significantly increased. Therefore, 60 dB noise and 200 Lux light were selected in the subsequent experiments. Compared with Con group, the horizontal score and vertical score in the open field test in LPS group were significantly decreased. There were no significant differences in the proportion of freezing time, the cerebral contents of EB and IL-6, the serum levels of melatonin and cortisol, and the hippocampal expressions of ZO-1, Claudin-5 and caspase-3. Compared with LPS group, the horizontal score, vertical score and the percentage of freezing time in LPS+60 dB group, LPS+200 Lux group and LPS+MS group were significantly reduced [horizontal score: 73.8±9.7, 80.3±9.4, 64.5±8.3 vs. 103.6±15.5; vertical score: 9.4±1.7, 11.2±1.9, 6.8±0.9 vs. 15.9±2.8; the percentage of freezing time: (45.3±4.7)%, (53.3±5.8)%, (42.1±5.1)% vs. (66.1±6.3)%], the serum level of melatonin was significantly decreased (ng/L: 53.62±6.20, 44.25±6.41, 45.33±5.84 vs. 74.39±7.54), the serum level of cortisol was significantly increased (nmol/L: 818.34±95.53, 710.04±65.41, 989.73±91.63 vs. 398.82±72.59), the levels of EB, IL-6 in the brain tissue were significantly increased [EB (μg/g): 2.80±0.35, 2.38±0.31, 3.24±0.42 vs. 1.59±0.26; IL-6 (ng/g): 31.56±4.11, 26.69±3.75, 37.47±4.56 vs. 16.28±2.69], the expressions of ZO-1 and Claudin-5 were significantly decreased (ZO-1/β-actin: 0.37±0.04, 0.32±0.05, 0.24±0.04 vs. 0.80±0.09; Claudin-5/β-actin: 0.62±0.08, 0.47±0.06, 0.35±0.05 vs. 0.97±0.20), and the expression of cleaved caspase-3 was significantly increased (caspase-3/β-actin: 0.56±0.06, 0.39±0.04, 0.72±0.12 vs. 0.20±0.03), with statistically significant differences (all P < 0.05). 60 dB noise, 200 Lux light or mechanical stimulation for 96 hours could inhibit the secretion of serum melatonin, promote the secretion of cortisol, and activate neuroinflammation in septic rats, and lead to neuronal apoptosis in hippocampus and hyper-permeability of blood-brain barrier, which in turn could cause sleep disturbance and cognitive impairment.

Objective To explore the effect of Ulinastatin on blood brain barrier (BBB) and apoptosis of neural cells in septic rats.Methods Fifty-two clean level male Sprague-Dawley rats were randomly (random number table) divided into six groups:Sham groups at 6 h and 24 h,each group with six rats.Sepsis groups (CLP) and Ulinastatin treated groups (UTI) at 6 h and 24 h,each group with ten rats.In CLP and UTI groups,cecal ligation and puncture (CLP) were performed to induce sepsis.Sham group was only opened and closed abdomen.Ulinastatin (50 000 U/kg) was administered via femoral vein 1 h after CLP.The same volume of saline instead of Ulinastatin was administered in Sham and CLP groups.The neurological status was assessed by Neurological Deficit Scale Scores (NDSS) at 6 h and 24 h after CLP.Then the brain was harvested for HE staining and weighing water content.The BBB permeability was assayed by Evans Blue dye extravasations.Apoptosis of neural cells were detected by TUNEL immune fluorescence.Statistical analysis was performed with SPSS version 13.0,ANOVA was used for multiple groups comparison and t-test for paired comparison.Results The Neurological Deficit Scale Scores of UTI group was lower than Sham group (P ＜ 0.05) but higher than that of CLP group (P ＜ 0.05).Swelling,degeneration and edema were observed in cerebral cortex and hippocampal neurons in CLP group through light microscope,and were more serious than those in UTI group.Compared with UTI 24 h group,BBB permeability of CLP 24 h group significantly rose (P ＜ 0.05).The number of apoptosis of neural cells increased more in CLP group than it did in UTI group (P ＜ 0.05).Conclusions Ulinastatin could protect the cerebral tissue in septic rats by alleviating the damage of BBB and reducing the apoptosis of neural cells. Key words: Sepsis; Cerebral injury; Cecal ligation and puncture; Ulinastatin; Evans blue; Blood brain barrier; Immune fluorescence; Apoptosis

The effects of hyperbaric oxygen therapy on blood–brain barrier permeability in septic rats

Objective To evaluate the effects of edaravone on the permeability of blood-brain barrier in septic rats.Methods Ninety male Sprague-Dawley rats,weighing 200-250 g,were randomly divided into 3 groups (n=30 each):control group (group C),sepsis group (group lipopolysaccharide (LPS)) and edaravone group (group E).Sepsis was induced by injection of LPS 10 mg/kg via the femoral vein in LPS and E groups.After LPS injection,edaravone 3.0 mg/kg was injected intravenously every 2h for 7 times in group E.The equal volume of normal saline was administered instead of edaravone in C and LPS groups.At 2,6 and 12h after LPS injection,5 rats were chosen and Evan's blue (EB) was injected via the femoral vein,and then the rats were sacrificed and brain tissues were removed for determination of EB and water contents.Another 5 rats were chosen and blood samples were taken from the femoral artery for measurement of serum MDA concentration,and then the rats were sacrificed and the brain tissue was harvested for microscopic examination.Results Compared with group C,brain water and EB contents were significantly increased at 6 and 12h after LPS injection,and the serum MDA concentration was increased at 2,6 and 12h after LPS injection in LPS and E groups (P ＜ 0.05).Compared with group LPS,brain water and EB contents were significantly decreased at 6 and 12h after LPS injection,and serum MDA concentrations were decreased at 2,6 and 12h after LPS injection in group E (P ＜ 0.05).Sepsis-induced pathological changes were significantly attenuated in group E.Conclusion Edaravone can decrease the permeability of blood-brain barrier,attenuate brain edema and brain injury in septic rats,and reduction of oxygen free radical production may be involved in the mechanism. Key words: Free radical scavengers; Sepsis; Blood-brain barrier

Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.

Glycemic control with insulin attenuates sepsis-associated encephalopathy by inhibiting glial activation via the suppression of the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways in septic rats

ObjectivesDelirium is a prominent symptom of sepsis-associated encephalopathy (SAE) and is highly prevalent in septic patients hospitalized in the intensive care unit, being closely connected with raised mortality rates. Acute hyperglycemia (AH) has been recognized as a separate risk factor for delirium and a worse prognosis in critically sick patients. Nevertheless, the exact contribution of AH to the advancement of SAE is still unknown.MethodsThis research retrospectively evaluated the connection between blood glucose levels (BGLs) and the incidence of delirium and death rates in septic patients in the ICU of a tertiary comprehensive hospital. In addition, a septic rat model was induced through cecal ligation and puncture (CLP), after which continuous glucose infusion was promptly initiated via a central venous catheter post-surgery to evaluate the potential implications of AH on SAE. Next, septic rats were assigned to four groups based on target BGLs: high glucose group (HG, ≥ 300 mg/dL), moderate glucose group (MG, 200–300 mg/dL), normal glucose group (NG, < 200 mg/dL), and a high glucose insulin-treated group (HI, 200–300 mg/dL) receiving recombinant human insulin treatment (0.1 IU/kg/min). The sham group (SG) received an equivalent volume of saline infusion and denoted the NG group. The effects of AH on neuroinflammation and cognitive function in septic rats were evaluated using behavioral tests, histopathological examination, TUNEL staining, ELISA, and Western blot. The effects of glucose levels on microglial activation and glucose metabolism following lipopolysaccharide (LPS, 1 μg/mL) exposure were assessed using CCK8 assay, qRT-PCR, Western blot, and ELISA.ResultsOur findings revealed that AH during sepsis was a separate risk factor for delirium and assisted in predicting delirium occurrence. AH raised the levels of systemic and central inflammatory cytokines in septic rats, promoting neuronal apoptosis, blood–brain barrier disruption, and cognitive impairment. In addition, both in vivo and in vitro, an elevated glucose challenge increased the ChREBP, HIF-1α, glycolytic enzymes, and inflammatory cytokines expressions in microglia after exposure to CLP or LPS.ConclusionsThese results collectively suggest that hyperglycemia can exacerbate neuroinflammation and delirium by enhancing microglial glycolysis under septic conditions, potentially mediated by upregulation of the ChREBP/HIF-1α signaling pathway.Graphical abstract

Oncostatin M (OSM) is a member of the interleukin (IL)-6 family cytokines. We previously demonstrated that OSM induces blood-brain barrier (BBB) impairment. However, functional characterization of IL-6 family cytokines in BBB regulation and the cytokine-related intracellular signaling pathway remain unclear. In this study, we demonstrate that among IL-6 family cytokines, including IL-6 and leukemia inhibitory factor (LIF), OSM is the most potent molecule for inducing BBB dysfunction via prolonged activation of signal transducer and activator of transcription (STAT) 3 following Janus-activated kinase (JAK) activation. OSM but not IL-6 and LIF (100 ng/mL for 24 hours) markedly produced increased sodium fluorescein permeability and decreased transendothelial electrical resistance in rat brain endothelial cell (RBEC) monolayers. This OSM-induced BBB dysfunction was accompanied by decreased levels of claudin-5 expression in RBECs, which were ameliorated by JAK inhibitor. We examined the time-course of STAT3 phosphorylation in RBECs treated with OSM, IL-6, and LIF. OSM upregulated STAT3 phosphorylation levels during a 24 hours period with a peak at 10 minutes. While IL-6 and LIF transiently increased phosphorylated STAT3 at 10 minutes after addition, this phosphorylation decreased during the period from 1 to 24 hours after addition. These findings suggest that OSM-induced sustained increases in STAT3 phosphorylation levels largely contribute to BBB impairment. Thus, elevated OSM levels and activation of brain endothelial JAK/STAT3 signaling pathway under pathological conditions should be considered as a possible hallmark for induction and development of BBB impairment.

IntroductionPermeability changes in the blood–brain barrier (BBB) and their possible contribution to brain edema formation have a crucial role in the pathophysiology of septic encephalopathy. Magnesium sulfate has been shown to have a protective effect on BBB integrity in multiple experimental models. In this study we determine whether magnesium sulfate administration could have any protective effects on BBB derangement in a rat model of sepsis.MethodsThis randomized controlled experimental study was performed on adult male Sprague–Dawley rats. Intraperitoneal sepsis was induced by using the infected fibrin–thrombin clot model. To examine the effect of magnesium in septic and sham-operated rats, a dose of 750 μmol/kg magnesium sulfate was given intramuscularly immediately after surgery. Control groups for both infected and sham-operated rats were injected with equal volume of saline. Those rats surviving for 24 hours were anesthetized and decapitated for the investigation of brain tissue specific gravity and BBB integrity by the spectrophotometric assay of Evans blue dye extravasations. Another set of experiments was performed for hemodynamic measurements and plasma magnesium level analysis. Rats were allocated into four parallel groups undergoing identical procedures.ResultsSepsis significantly increased BBB permeability to Evans blue. The dye content of each hemisphere was significantly lower in the magnesium-treated septic rats (left hemisphere, 0.00218 ± 0.0005; right hemisphere, 0.00199 ± 0.0007 [all results are means ± standard deviation]) than in control septic animals (left hemisphere, 0.00466 ± 0.0002; right hemisphere, 0.00641 ± 0.0003). In septic animals treated with magnesium sulfate, specific gravity was higher (left hemisphere, 1.0438 ± 0.0007; right hemisphere, 1.0439 ± 0.0004) than in the untreated septic animals (left hemisphere, 1.0429 ± 0.0009; right hemisphere, 1.0424 ± 0.0012), indicating less edema formation with the administration of magnesium. A significant decrease in plasma magnesium levels was observed 24 hours after the induction of sepsis. The dose of magnesium that we used maintained the baseline plasma magnesium levels in magnesium-treated septic rats.ConclusionsMagnesium administration attenuated the increased BBB permeability defect and caused a reduction in brain edema formation in our rat model of intraperitoneal sepsis.

Platonin preserves blood–brain barrier integrity in septic rats

Blood-brain barrier derangement in sepsis: Cause of septic encephalopathy?

Effects of hydroxyethyl starch (130 kD) on brain inflammatory response and outcome during normotensive sepsis