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

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

doi:10.2119/molmed.2014.00143

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.

Highlights

Acute illness and hospitalization is often accompanied by learning and memory impairments, especially among elderly patients, a steadily growing portion of the surgical and intensive care unit (ICU) populations [1]
In surgery-induced inflammation, we reported that α7 nAChR signaling attenuates postoperative cognitive decline by modulating endothelia function at the blood-brain barrier (BBB) and preventing macrophage infiltration into the central nervous system (CNS) [12]
In this study we demonstrated that postoperative complications such as infection prolong the neuroinflammatory response after surgical trauma and worsen cognitive decline

Summary

Introduction

Acute illness and hospitalization is often accompanied by learning and memory impairments, especially among elderly patients, a steadily growing portion of the surgical and intensive care unit (ICU) populations [1]. Postoperative cognitive dysfunction (POCD) associates with higher morbidity and mortality (even when propensity matched for comorbidities), including increase in functional disability and rates of admission to long-term care institutions; the presence of postoperative cognitive decline significantly increases the costs to healthcare [2]. Ing changes in acute mental function remain unclear, multiple risk factors, in particular age, surgical procedures (including cardiac and orthopedic in particular) and infections, have been linked to the development of POCD [3,4]. Neuroinflammation initiated by extra-central nervous system (CNS) surgical trauma, has been advanced as a key component in the pathogenesis of surgery-induced cognitive dysfunction; the mechanisms whereby neuroinflammation impairs behavior in the perioperative period remain unclear [5]. Soluble mediators from the periphery can exert multiple effects on the brain, contributing to “sick-

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