Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model

Abstract

BackgroundSystemic 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.MethodsIn 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.ResultsMice 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1163-z) contains supplementary material, which is available to authorized users.

Surgery, neuroinflammation and cognitive impairment

“…Conversely, the inhibition of COX-2 provides ibuprofen with its analgesic, antipyretic, and anti-inflammatory properties. Research on mice by Huang et al [ 80 ], has demonstrated improved cognitive performance, reduced systemic inflammation and glial activation upon the utilisation of ibuprofen perioperatively. Pre-operative administration of IV ibuprofen has been shown to improve post-operative cognitive function in the clinical setting, where the level of cytokines, cortisol, and catecholamines were reduced [ 81 ].…”

Chemokine CXCL13 acts via CXCR5-ERK signaling in hippocampus to induce perioperative neurocognitive disorders in surgically treated mice

“…PNDs not only increase the burden on the healthcare system but also lead to postoperative long-term disability and even mortality. The use of volatile anesthetics during surgery has long been suspected of increasing risk of PNDs [ 4 , 5 ]. As the number of surgeries continues to increase, PNDs are expected to become an epidemic [ 1 ].…”

“…As the number of surgeries continues to increase, PNDs are expected to become an epidemic [ 1 ]. Increasing evidence suggests that PNDs involve neuroinflammation in the hippocampus, at least in their early stages [ 2 , 4 ]. Under certain conditions, secreted chemokines contribute to neuroinflammation in the central nervous system (CNS) [ 6 – 8 ].…”

Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?

“…Both systemic inflammation and neuroinflammation, particularly in the hippocampus, triggered by peripheral surgery trauma or anesthesia, have been proposed to be involved in the observed cognitive deficits [21][22][23][24]. Elevated levels of proinflammatory cytokines, such as interleukin-(IL-) 6, IL-1β, and tumor necrosis factor (TNF)-α, have been reported after surgery and may be related to POCD [25]. For instance, Xu et al observed elevated levels of IL-6 following abdominal surgery in the elderly, which positively correlated with decline in cognitive function [26].…”