• Br J Anaesth · Mar 2018

    Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice.

    • J Hu, X Feng, M Valdearcos, D Lutrin, Y Uchida, S K Koliwad, and M Maze.
    • Department of Anesthesia and Perioperative Care and Center for Cerebrovascular Research, University of California, San Francisco, CA, USA; Department of Anesthesia, Tongling People's Hospital, Tongling, Anhui 244000, People's Republic of China.
    • Br J Anaesth. 2018 Mar 1; 120 (3): 537-545.

    BackgroundPerioperative neurocognitive disorders (PND) result in long-term morbidity and mortality with no effective interventions available. Because interleukin-6 (IL-6), a pro-inflammatory cytokine, is consistently up-regulated by trauma, including after surgery, we determined whether IL-6 is a putative therapeutic target for PND in a mouse model.MethodsFollowing institutional approval, adult (12-14 weeks) male C57/Bl6 mice were pretreated with the IL-6 receptor (IL6R) blocking antibody tocilizumab prior to open tibia fracture with internal fixation under isoflurane anaesthesia. Inflammatory and behavioural responses in a trace fear conditioning (TFC) paradigm were assessed postoperatively. Separately, the effects of IL-6 administration or of depletion of bone marrow-derived monocytes (BM-DMs) with clodrolip on the inflammatory and behavioural responses were assessed. Blood brain barrier disruption, hippocampal microglial activation, and infiltration of BM-DMs were each assessed following IL-6 administration.ResultsThe surgery-induced decrement in freezing time in the TFC assay, indicative of cognitive decline, was attenuated by tocilizumab (P<0.01). The surgery-induced increase in pro-inflammatory mediators was significantly reduced by tocilizumab. Exogenously administered IL-6 significantly impaired freezing behaviour (P<0.05) and up-regulated pro-inflammatory cytokines; both responses were prevented by depletion of BM-DMs. IL-6 disrupted the blood brain barrier, and increased hippocampal activation of microglia and infiltration of BM-DMs.ConclusionsIL-6 is both necessary and sufficient to produce cognitive decline. Following further preclinical testing of its perioperative safety, the IL6R blocker tocilizumab is a candidate for prevention and/or treatment of PND.Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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