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

Abstract：

BACKGROUND:Perioperative 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. METHODS:Following 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. RESULTS:The 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. CONCLUSIONS:IL-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.

journal_name

Br J Anaesth

journal_title

British journal of anaesthesia

authors

Hu J,Feng X,Valdearcos M,Lutrin D,Uchida Y,Koliwad SK,Maze M

doi

10.1016/j.bja.2017.11.096

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

537-545

issue

eissn

0007-0912

issn

1471-6771

pii

S0007-0912(17)54179-3

journal_volume

120

pub_type

杂志文章

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