title: Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice.
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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.|Department of Anesthesia and Perioperative Care, UCSF Medical Center, San Francisco, California, United States of America.
authors.forename: Niccolò
authors.initials: N
authors.lastname: Terrando
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.|Department of Anesthesia and Perioperative Care, UCSF Medical Center, San Francisco, California, United States of America.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Gladstone Institute of Neurological Disease, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jae Kyu
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.|Department of Women's and Children's Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Newton
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, London, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Monaco
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, London, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.affiliation: Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, United Kingdom.
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
authors.affiliation: Gladstone Institute of Neurological Disease, University of California San Francisco, San Francisco, California, United States of America.|Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.affiliation: Department of Anesthesia and Perioperative Care, UCSF Medical Center, San Francisco, California, United States of America.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001372:Aza Compounds / Q000494:pharmacology / Q000627:therapeutic use; D039481:CD11b Antigen / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004147:Dioxins / Q000494:pharmacology / Q000627:therapeutic use; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D050723:Fractures, Bone / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages; D008297:Male; D008568:Memory / Q000187:drug effects; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011183:Postoperative Complications / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D013977:Tibia / Q000293:injuries*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001372:Aza Compounds; D039481:CD11b Antigen; D018679:Cholinergic Agonists; D016207:Cytokines; D004147:Dioxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D064569:alpha7 Nicotinic Acetylcholine Receptor; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C514026:PHA-568487E