Inflammatory signalling in postoperative cognitive dysfunctions

Major surgeries, such as cardiac or orthopaedic procedures in particular, expose the patient to extensive trauma, blood loss, and tissue injury; all of these factors effectively modulate the immune system to ultimately trigger an inflammatory response. Postoperative cognitive dysfunction (POCD), the condition being characterized by impairment of short and long-term memory, is one of common complicates following surgery. Recently, our data have demonstrated that neuroinflammation and microglia activation in the hippocampus following surgery are associated with cognitive decline. The aim of this thesis is to investigate the inflammatory signaling pathways specifically involved with POCD, with a particular interest between systemic inflammation and local inflammation in the brain following surgery. The data presented in this thesis introduce the general concepts and the involvement of inflammation in the etiology of cognitive dysfunctions using a mouse model of POCD. Upon the identification of specific pro-inflammatory markers both systemically and centrally and the delineation of the time course of events that characterize the inflammatory response following aseptic orthopaedic surgery, I describe how specific cellular signal pathways interact, mediate, and sustain this response. Following an initial non-specific approach using a general anti-inflammatory compound to identify whether inflammation plays a role in this scenario, I have exploited this model into a wide range of knockouts animals in the attempt of identifying specific signaling mechanisms and upstream receptors that mediate the behavioral abnormality following surgery. In order to achieve this, I have compared the inflammatory events after aseptic surgery with the response after a defined infectious stimulus, to ultimately joint the two in the context of a postoperative complication. In conclusion, inflammation clearly plays a pivotal role in mediating physiological as well as behavioral changes after surgery and infection. This thesis has started to unmask the signaling pathways involved with surgery and how anti-cytokine therapy can potentially ameliorate the associated cognitive dysfunction

Perioperative Neurocognitive Disorder: State of the Preclinical Science.

The purpose of this article is to provide a succinct summary of the different experimental approaches that have been used in preclinical postoperative cognitive dysfunction research, and an overview of the knowledge that has accrued. This is not intended to be a comprehensive review, but rather is intended to highlight how the many different approaches have contributed to our understanding of postoperative cognitive dysfunction, and to identify knowledge gaps to be filled by further research. The authors have organized this report by the level of experimental and systems complexity, starting with molecular and cellular approaches, then moving to intact invertebrates and vertebrate animal models. In addition, the authors' goal is to improve the quality and consistency of postoperative cognitive dysfunction and perioperative neurocognitive disorder research by promoting optimal study design, enhanced transparency, and "best practices" in experimental design and reporting to increase the likelihood of corroborating results. Thus, the authors conclude with general guidelines for designing, conducting and reporting perioperative neurocognitive disorder rodent research

The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction

INTRODUCTION: The impact of pro-inflammatory cytokines on neuroinflammation and cognitive function after lipopolysaccharide (LPS) challenge remains elusive. Herein we provide evidence that there is a temporal correlation between high-mobility group box 1 (HMGB-1), microglial activation, and cognitive dysfunction. Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability. METHODS: Endotoxemia was induced in wild-type and IL-1R-/- mice by intra peritoneal injection of E. Coli LPS (1 mg/kg). Markers of inflammation were assessed both peripherally and centrally, and correlated to behavioral outcome using trace fear conditioning. RESULTS: Increase in plasma tumor necrosis factor-alpha (TNFalpha) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1beta, IL-6 and HMGB-1 was more persistent, with detectable levels up to day three. A 15-fold increase in IL-6 and a 6.5-fold increase in IL-1beta mRNA at 6 hours post intervention (P < 0.001 respectively) was found in the hippocampus. Reactive microgliosis was observed both at days one and three, and was associated with elevated HMGB-1 and impaired memory retention (P < 0.005). Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis and ameliorated cognitive dysfunction without affecting HMGB-1 levels. Similar results were observed in LPS-challenged mice lacking the IL-1 receptor to those seen in LPS-challenged wild type mice treated with IL-1Ra. CONCLUSIONS: These data suggest that by blocking IL-1 signaling, the inflammatory cascade to LPS is attenuated, thereby reducing microglial activation and preventing the behavioral abnormality

Deferoxamine regulates neuroinflammation and iron homeostasis in a mouse model of postoperative cognitive dysfunction

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially amongst elderly patients. Neuroinflammation and iron homeostasis are key hallmarks of several neurological disorders. In this study, we investigated the role of deferoxamine (DFO), a clinically used iron chelator, in a mouse model of surgery-induced cognitive dysfunction and assessed its neuroprotective effects on neuroinflammation, oxidative stress, and memory function. METHODS: A model of laparotomy under general anesthesia and analgesia was used to study POCD. Twelve to 14 months C57BL/6J male mice were treated with DFO, and changes in iron signaling, microglia activity, oxidative stress, inflammatory cytokines, and neurotrophic factors were assessed in the hippocampus on postoperative days 3, 7, and 14. Memory function was evaluated using fear conditioning and Morris water maze tests. BV2 microglia cells were used to test the anti-inflammatory and neuroprotective effects of DFO. RESULTS: Peripheral surgical trauma triggered changes in hippocampal iron homeostasis including ferric iron deposition, increase in hepcidin and divalent metal transporter-1, reduction in ferroportin and ferritin, and oxidative stress. Microglia activation, inflammatory cytokines, brain-derived neurotropic factor impairments, and cognitive dysfunction were found up to day 14 after surgery. Treatment with DFO significantly reduced neuroinflammation and improved cognitive decline by modulating p38 MAPK signaling, reactive oxygen species, and pro-inflammatory cytokines release. CONCLUSIONS: Iron imbalance represents a novel mechanism underlying surgery-induced neuroinflammation and cognitive decline. DFO treatment regulates neuroinflammation and microglia activity after surgery

Disrupted neuroglial metabolic coupling after peripheral surgery

Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and72hpostsurgery. At 6hwedetect theproinflammatorycytokineIL-6inthehippocampus, followedupbyalterations in them RNA and protein expression of astrocyticandneuronal proteinsnecessaryfor optimal energysupplytothebrainandfor thereuptakeandrecycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction.This work was supported by a “Ramón y Cajal” fellowship (RYC-2014-15792 to A.G.-C.) from Spanish “Ministerio de Economía y Competitividad”, the Swedish Research Council, the confocal microscope used in the study by Knut and Alice Wallenberg Foundation (Grant KAW2008.0149), and NIH/NIA R01AG057525 to N.T

Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice

Abstract Introduction Acute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the α2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia-reperfusion induced kidney injury in vitro and in vivo. Methods In vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the α2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 μg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy. Results Pre- or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy. Conclusions Our data suggest that Dex likely activates cell survival signal pAKT via α2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection

Conserved YKL-40 changes in mice and humans after postoperative delirium

Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence (14%–50%) and likely association with inflammation, the exact mechanisms that underpin postoperative delirium are unclear. This project aimed to characterize systemic and central nervous system (CNS) inflammatory changes following surgery in mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the “Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults” (INTUIT; NCT03273335) study were compared to murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well established orthopedic surgical model in the FosTRAP reporter mouse we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing evidence for a YKL-40 role in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were similarly increased after surgery, with a trend toward a greater postoperative plasma YKL-40 increase in patients with delirium. However, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in the blood-brain barrier (BBB) as early as 9 h after surgery in mice, which warrants more detailed and acute evaluations of BBB integrity following surgery in humans. Together, these results provide a nuanced understanding of neuroimmune interactions underlying postoperative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms

The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap.

peer reviewedPeripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer's disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood-brain barrier and other components of the neuro-immune axis in Alzheimer's disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer's disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology

The immune response of the human brain to abdominal surgery

ObjectiveSurgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short- and long-term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function.MethodsEight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed.ResultsPatients showed a global downregulation of gray matter [11 C]PBR28 binding of 26 ± 26% (mean ± standard deviation) at 3 to 4 days postoperatively compared to baseline (p = 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-α in blood displayed a reduction (41 ± 39%) on the 3rd to 4th postoperative day, corresponding to changes in [11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [11 C]PBR28 binding (p = 0.027).InterpretationThis study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. Ann Neurol 2017;81:572-582

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions