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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 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.

Original publication

DOI

10.2119/molmed.2014.00143

Type

Journal article

Journal

Mol Med

Publication Date

17/03/2015

Volume

20

Pages

667 - 675

Keywords

Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Aza Compounds, CD11b Antigen, Cell Line, Cells, Cultured, Cholinergic Agonists, Cognition Disorders, Cytokines, Dioxins, Endotoxemia, Fractures, Bone, Hippocampus, Lipopolysaccharides, Macrophages, Male, Memory, Mice, Inbred C57BL, NF-kappa B, Postoperative Complications, Rats, Tibia, alpha7 Nicotinic Acetylcholine Receptor