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Resolving postoperative neuroinflammation and cognitive decline

Authors

  • Niccolò Terrando PhD,

    1. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
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  • Lars I. Eriksson MD, PhD,

    1. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
    2. Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institute, Stockholm, Sweden
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  • Jae Kyu Ryu PhD,

    1. Gladstone Institute of Neurological Disease, University of California at San Francisco, San Francisco, CA
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  • Ting Yang MD, PhD,

    1. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
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  • Claudia Monaco MD, PhD,

    1. Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom
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  • Marc Feldmann FMedSci, FAA, FRS,

    1. Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom
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  • Malin Jonsson Fagerlund MD, PhD,

    1. Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institute, Stockholm, Sweden
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  • Israel F. Charo MD, PhD,

    1. Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, CA
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  • Katerina Akassoglou PhD,

    1. Gladstone Institute of Neurological Disease, University of California at San Francisco, San Francisco, CA
    2. Department of Neurology, University of California at San Francisco, San Francisco, CA
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  • Mervyn Maze MB, ChB

    Corresponding author
    1. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
    • Department of Anesthesia and Perioperative Care, 521 Parnassus Avenue, C455, San Francisco, CA 94143-0648
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Abstract

Objective:

Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response that, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved.

Methods:

C57BL/6J, Ccr2RFP/+Cx3cr1GFP/+, IkkF/F mice and LysM-Cre/IkkF/F mice underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood–brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied.

Results:

Peripheral surgery disrupts the BBB via release of tumor necrosis factor-alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage-specific deletion of Ikappa B kinase (IKK)β, a central coordinator of TNFα signaling through activation of nuclear factor (NF) κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation-resolving pathway, prevents TNFα-induced NF-κB activation, macrophage migration into the hippocampus, and cognitive decline following surgery.

Interpretation:

These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline. ANN NEUROL 2011;70:986–995

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