Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice

Mol Med. 2015 Mar 17;20(1):667-75. doi: 10.2119/molmed.2014.00143.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Aza Compounds / pharmacology
  • Aza Compounds / therapeutic use
  • CD11b Antigen / metabolism
  • Cell Line
  • Cells, Cultured
  • Cholinergic Agonists / pharmacology
  • Cholinergic Agonists / therapeutic use*
  • Cognition Disorders / blood
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / metabolism
  • Cytokines / blood
  • Dioxins / pharmacology
  • Dioxins / therapeutic use
  • Endotoxemia / blood
  • Endotoxemia / drug therapy*
  • Endotoxemia / metabolism
  • Fractures, Bone / blood
  • Fractures, Bone / drug therapy*
  • Fractures, Bone / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Lipopolysaccharides
  • Macrophages
  • Male
  • Memory / drug effects
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Postoperative Complications / blood
  • Postoperative Complications / drug therapy*
  • Postoperative Complications / metabolism
  • Rats
  • Tibia / injuries*
  • alpha7 Nicotinic Acetylcholine Receptor / agonists*


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Aza Compounds
  • CD11b Antigen
  • CD68 protein, mouse
  • Cholinergic Agonists
  • Cytokines
  • Dioxins
  • Lipopolysaccharides
  • NF-kappa B
  • PHA-568487E
  • alpha7 Nicotinic Acetylcholine Receptor