4.7 Article

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

Journal

MOLECULAR MEDICINE
Volume 20, Issue -, Pages 667-675

Publisher

FEINSTEIN INST MED RES
DOI: 10.2119/molmed.2014.00143

Keywords

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Funding

  1. Anesthesia Department, UCSF
  2. European Society of Anaesthesiology
  3. Karolinska Institutet Funds
  4. NIH [R01 NS052189, R21 NS082976]
  5. Mathilda and Terence Kennedy Institute of Rheumatology Trust
  6. [R01 GM104194]

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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 alpha 7 subtype nicotinic acetylcholine receptor (alpha 7 nAChR) agonist 2 h after LPS significantly improved neuroinflammation and hippocampal-dependent memory dysfunction. Modulation of nuclear factor-kappa B (NF-kappa B) 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.

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