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Molecular Medicine

, Volume 20, Issue 1, pp 667–675 | Cite as

Stimulation of the α7 Nicotinic Acetylcholine Receptor Protects against Neuroinflammation after Tibia Fracture and Endotoxemia in Mice

  • Niccolò Terrando
  • Ting Yang
  • Jae Kyu Ryu
  • Phillip T. Newton
  • Claudia Monaco
  • Marc Feldmann
  • Daqing Ma
  • Katerina Akassoglou
  • Mervyn Maze
Research Article

Abstract

Surgery and critical illness often associate with cognitive decline. Surgical trauma or infection can lead independently to learning and memory impairments via similar, but not identical, cellular signaling of the innate immune system that promotes neuroinflammation. In this study we explored the putative synergism between aseptic orthopedic surgery and infection, the latter reproduced by postoperative lipopolysaccharide (LPS) administration. We observed that surgery and LPS augmented systemic inflammation up to postoperative d 3 and this was associated with further neuroinflammation (CD11b and CD68 immunoreactivity) in the hippocampus in mice compared with those receiving surgery or LPS alone. Administration of a selective α7 subtype nicotinic acetylcholine receptor (α7 nAChR) agonist 2 h after LPS significantly improved neuroinflammation and hippocampal-dependent memory dysfunction. Modulation of nuclear factor-kappa B (NF-κB) activation in monocytes and regulation of the oxidative stress response through nicotinamide adenine dinucleotide phosphate (NADPH) signaling appear to be key targets in modulating this response. Overall, these results suggest that it may be conceivable to limit and possibly prevent postoperative complications, including cognitive decline and/or infections, through stimulation of the cholinergic antiinflammatory pathway.

Notes

Acknowledgments

This work was supported by R01 GM104194 (M Maze), the Anesthesia Department, UCSF (M Maze), a research grant program of the European Society of Anaesthesiology and Karolinska Institutet Funds (N Terrando), NIH grants R01 NS052189 and R21 NS082976 (K Akassoglou) and the Mathilda and Terence Kennedy Institute of Rheumatology Trust (M Feldmann, C Monaco).

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© The Author(s) 2014

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Authors and Affiliations

  • Niccolò Terrando
    • 1
    • 2
  • Ting Yang
    • 1
    • 2
  • Jae Kyu Ryu
    • 3
  • Phillip T. Newton
    • 1
    • 4
  • Claudia Monaco
    • 5
  • Marc Feldmann
    • 5
  • Daqing Ma
    • 6
  • Katerina Akassoglou
    • 3
    • 7
  • Mervyn Maze
    • 2
  1. 1.Department of Physiology and PharmacologyKarolinska InstituteStockholmSweden
  2. 2.Department of Anesthesia and Perioperative CareUCSF Medical CenterSan FranciscoUSA
  3. 3.Gladstone Institute of Neurological DiseaseUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Department of Women’s and Children’s HealthAstrid Lindgren Children’s Hospital, Karolinska University HospitalStockholmSweden
  5. 5.Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordLondonUK
  6. 6.Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of MedicineImperial College London, Chelsea & Westminster HospitalLondonUK
  7. 7.Department of NeurologyUniversity of California San FranciscoSan FranciscoUSA

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