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. 2018 May 17;15(1):147.
doi: 10.1186/s12974-018-1163-z.

Evidence of the Impact of Systemic Inflammation on Neuroinflammation From a Non-Bacterial Endotoxin Animal Model

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Free PMC article

Evidence of the Impact of Systemic Inflammation on Neuroinflammation From a Non-Bacterial Endotoxin Animal Model

Chunxia Huang et al. J Neuroinflammation. .
Free PMC article

Abstract

Background: Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term.

Methods: In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed.

Results: Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus.

Conclusions: Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.

Keywords: Ibuprofen; Neuroinflammation; Postoperative cognitive dysfunction; Sevoflurane; Tau proteins.

Conflict of interest statement

Ethics approval

All experimental protocols and animal handling procedures were approved by CULATR (Ref. No. 3437-14).

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Laparotomy induced acute and persistent peripheral inflammation and neuroinflammation. a Relative mRNA levels of pro- and anti-inflammatory cytokines in the liver, frontal cortex, and hippocampus showed a pro-inflammatory state at 4 h after laparotomy. b Cytokines protein expressions measured by MILLIPLEX assay of whole tissue lysates at 24 h for the brain and liver. a, b n = 7–8; *p < 0.05, **p < 0.01, ***p < 0.001. c Systemic inflammation was determined by the increases of pro-inflammatory cytokines in the plasma on POD 1, 3, and 14. At 24 and 72 h, n = 7–8; at 14d, n = 8–12; *p < 0.05, **p < 0.01. For IL-1β, LAP+Ibu vs. LAP, p = 0.0685. d On postoperative day (POD) 14, similar cytokine concentration in the brain after sevoflurane anesthesia or laparotomy under sevoflurane anesthesia with or without ibuprofen consumption (n = 8–12)
Fig. 2
Fig. 2
Activation of glia in the brain from surgical mice. a In the motor cortex, the number of Iba1+ microglia was quantified by using Kruskal-Wallis test with Dunn’s correction, Kruskal-Wallis statistic = 15.11, LAP vs. SEVO, **p = 0.0051; LAP+Ibu vs. LAP, **p = 0.0077. In the sensory cortex, the cell count of Iba1+ microglia was analyzed by using Kruskal-Wallis test with Dunn’s correction, Kruskal-Wallis statistic = 21.76, *p = 0.03, **p = 0.0023, and ***p = 0.0008. In the hippocampus, the number of Iba1+ microglia was quantified by using one-way ANOVA (n = 3–5, F = 5.492; LAP vs. CON, *p = 0.0218; LAP vs. SEVO, **p = 0.0041; LAP+Ibu vs. LAP, *p = 0.0182). Dots in the graphs represent the mean value of the four brain sections per mouse. b The percentage of cell body to the total cell size of Iba1+ microglia was quantified by using one-way ANOVA (n = 3–5). In the motor cortex, F = 7.146; LAP vs. SEVO, *p = 0.0134; LAP+Ibu vs. LAP, *p = 0.0125. In the sensory cortex, F = 10.99; LAP vs. CON, *p = 0.0226; LAP vs. SEVO, *p = 0.0017; LAP+Ibu vs. LAP, *p = 0.0107. In the hippocampus, F = 16.99; LAP vs. CON, *p = 0.0193; LAP vs. SEVO, **p = 0.0002; LAP+Ibu vs. LAP, **p = 0.0029. Dots in the graphs represent the mean value of the four brain sections per mouse. c Representative confocal microphotographs presented the activation of Iba1+ microglia in the hippocampus. d The activation of GFAP+ astrocyte was quantified using one-way ANOVA. In the motor cortex (left), F = 8.969, *p = 0.0452, and **p = 0.0018. In the sensory cortex (right), F = 12.52, *p = 0.0165, **p = 0.0045, and ***p = 0.0007
Fig. 3
Fig. 3
Tau protein phosphorylation following sevoflurane anesthesia or laparotomy on POD 14. Tau phosphorylation levels at different phosphorylation sites recognized by antibodies S404 (Ser404), AT8 (Ser202/Thr205), AT180 (Thr231/Ser235), and panTau in the a frontal cortex and b hippocampus (n = 8, *p < 0.05, **p < 0.01, ***p < 0.001)
Fig. 4
Fig. 4
Tau protein phosphorylation-related signaling pathways following sevoflurane anesthesia or laparotomy on POD 14. a & b Differential changes of GSK3β and phosphatase (PP2A) in the frontal cortex (a) and hippocampus (b). Relative levels of p-GSK3β (Ser9)/GSK3β and p-PP2A (Tyr307) in Western blot analysis. c & d Relative levels of p-Jak2 (Tyr1007/1008)/Jak2, p-Stat3 (Tyr705)/Stat3, p-ERK/ERK, and p-JNK/JNK in the frontal cortex (a) and hippocampus (d) were evaluated by using Western blot analysis. For each panel, n = 8, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 5
Fig. 5
Persistent cognitive impairment during postoperative period. a Body weights as percentage of baseline were analyzed using a two-way ANOVA followed by Bonferroni’s post hoc test (F2,103 = 42.75; LAP vs. SEVO, *p = 0.0445, **p = 0.0059, ***p < 0.0001; LAP vs. CON, ###p < 0.0001; on POD 14, LAP vs. SEVO, p = 0.0531). b Rectal temperature was analyzed by two-way ANOVA followed by Bonferroni’s post hoc test (**p = 0.0071, F = 2.588). c In the open filed test, locomotor activity and anxiety indicated by grid crossing frequency and central exploration time respectively on POD 1, 3, and 14. d In the Y-maze test, longer escape latency and greater error number showed working memory deficits on POD 1, 3, and 14. e In the novel object recognition (NOR) test, discrimination index (DI) was the ratio of exploration time of one object to two objects, old object (A) to (A + A) on POD 12, or new object (B) to (A + B) on POD 13. There was no object and location preference during the familiarization session. ae n = 9–12, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 6
Fig. 6
Perioperative ibuprofen intervention prevented cognitive dysfunction. a Percentage body weight changes with and without ibuprofen administration. Two-way ANOVA followed by Bonferroni’s post hoc test (***p = 0.0001, F1,108 = 20.06). b Reduction in DI decline in the NOR test after laparotomy with ibuprofen treatment. ***p = 0.0002, t = 4.301; Student’s two-tailed t test. c Reduced error number, Mann-Whitney test, Mann-Whitney U statistic = 14, **p = 0.0029, and shorter latency in the Y-maze test, *p = 0.0142, t = 2.698; Student’s two-tailed t test. ac n = 11 in LAP group and n = 14 in LAP+Ibu group
Fig. 7
Fig. 7
Perioperative ibuprofen intervention prevented tau protein hyperphosphorylation induced by laparotomy. Ibuprofen attenuated tau phosphorylation without affecting total tau in the a frontal cortex and b hippocampus. For each panel, n = 6, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 8
Fig. 8
Perioperative ibuprofen intervention inhibited the activation of tau phosphorylation related kinases and cellular stress signaling pathways induced by laparotomy. a & b Effect of ibuprofen on GSK3β and phosphatase (PP2A) in the frontal cortex (a) and hippocampus (b), c & d stress (Jak2/Stat3 and JNK) and cell survival (ERK) signaling pathways in the frontal cortex (c) and hippocampus (d). For each panel, n = 6, *p < 0.05, **p < 0.01, ***p < 0.001

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