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

Hu, Jun; Feng, Xiaomei; Valdearcos, Martín; Lutrin, David; Uchida, Yoshiyuki; Koliwad, Suneil K.; Maze, Mervyn

doi:10.1016/j.bja.2017.11.096

Cited by 116 publications

(103 citation statements)

References 32 publications

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“…aiming to reveal the underlying mechanisms of POCD and POD. Among these types of surgical trauma, open tibial fracture with intramedullary fixation (Cibelli et al, 2010;Terrando et al, 2010Terrando et al, , 2011Degos et al, 2013;Hu et al, 2018;Ni et al, 2018) and FIGURE 10 | Hippocampal inflammatory trend after tibial fracture surgery. (A) TNF-α mRNA levels were significantly increased on day 1 and returned to control levels on day 7.…”

Section: Discussionmentioning

confidence: 99%

“…Compared with exploratory laparotomy, we found that tibial fracture surgery was more suitable for models of POCD and POD in mice, considering its higher survival rate and more standardized procedure (unpublished data). Besides, considering that motor activity was not significantly changed after tibial fracture surgery in most studies (Cibelli et al, 2010;Terrando et al, 2010Terrando et al, , 2011Degos et al, 2013;Hu et al, 2018;Ni et al, 2018), we decided to apply this trauma model in the present study. Unfortunately, however, we found that motor activity was actually affected after tibial surgery (Figure 2), which might be attributed to the higher age of the mice we used (12-14 months) while the studies mentioned above used adult rodents around 3 months.…”

Section: Discussionmentioning

confidence: 99%

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The Investigation of Hippocampus-Dependent Cognitive Decline Induced by Anesthesia/Surgery in Mice Through Integrated Behavioral Z-Scoring

Meng

et al. 2020

Front. Behav. Neurosci.

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Objective: Patients undergoing major surgeries may experience certain cognitive decline, which is known as postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). We employed integrated behavioral Z-scoring introduced by Guilloux et al. (2011) to investigate the effects of fracture fixation under anesthesia on hippocampus-dependent memory in mice. Methods: ICR mice (12-14 months) underwent stabilized tibial fracture operation under sevoflurane anesthesia. They were subjected to a battery of successive hippocampusdependent tests following surgery, including open field test (OF), novel object recognition (NOR), fear conditioning test (FC), and Morris water maze (MWM). The integrated behavioral Z-scoring was applied to assess the hippocampus-dependent memory after anesthesia/surgery, and the association between the integrated behavioral Z-scores and hippocampal pro-inflammatory cytokines was explored. Results: Mice after anesthesia/surgery were found to have impaired hippocampusdependent memory in NOR, FC, and MWM but with different degrees in these aspects as represented by P-value and effect size. The integrated memory Z-scores based on principal parameters of the above three tests can reduced the variability and increase the comprehensiveness of behavioral results. However, we found no statistic associations between hippocampal pro-inflammatory cytokines and the integrated Z-scores, as the elevated cytokines quickly return to normal on postoperative day 3 and/or day 7. Conclusion: The integrated Z-score methodology could facilitate the interpretation of the anesthesia/surgery induced cognitive decline in mice and robustly quantify the behavioral phenotyping of hippocampus-dependent memory.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Investigation of Hippocampus-Dependent Cognitive Decline Induced by Anesthesia/Surgery in Mice Through Integrated Behavioral Z-Scoring

Meng

et al. 2020

Front. Behav. Neurosci.

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“…Systemic inflammation and pro-inflammatory cytokines released after surgery have been associated with changes in neuronal function and are highlighted as critical pathogenic mechanisms underlying cognitive decline in preclinical models. 16 , 17 , 18 Because SPMs provide both anti-inflammatory and pro-resolving actions without being immunosuppressive, 19 we tested the hypothesis that targeting macrophage trafficking into the brain using synthetic MaR1 will reduce neuroinflammation and improve cognitive outcome in a murine model of orthopaedic surgery. We also provide preliminary evidence that MaR1 levels can be measured in human cerebrospinal fluid (CSF) before and after surgery, raising the possibility that MaR1 levels could potentially play a role in resolving postoperative neuroinflammation in the human CNS.…”

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confidence: 99%

Maresin 1 attenuates neuroinflammation in a mouse model of perioperative neurocognitive disorders

Yang

Newton

et al. 2019

British Journal of Anaesthesia

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Background Resolution of inflammation is an active and dynamic process after surgery. Maresin 1 (MaR1) is one of a growing number of specialised pro-resolving lipids biosynthesised by macrophages that regulates acute inflammation. We investigated the effects of MaR1 on postoperative neuroinflammation, macrophage activity, and cognitive function in mice. Methods Adult male C57BL/6 ( n =111) and Ccr2 RFP/+ Cx3cr1 GFP/+ ( n =54) mice were treated with MaR1 before undergoing anaesthesia and orthopaedic surgery. Systemic inflammatory changes, bone healing, neuroinflammation, and cognition were assessed at different time points. MaR1 protective effects were also evaluated using bone marrow derived macrophage cultures. Results MaR1 exerted potent systemic anti-inflammatory effects without impairing fracture healing. Prophylaxis with MaR1 prevented surgery-induced glial activation and opening of the blood–brain barrier. In Ccr2 RFP/+ Cx3cr1 GFP/+ mice, fewer infiltrating macrophages were detected in the hippocampus after surgery with MaR1 prophylaxis, which resulted in improved memory function. MaR1 treatment also reduced expression of pro-inflammatory cell surface markers and cytokines by in vitro cultured macrophages. MaR1 was detectable in the cerebrospinal fluid of older adults before and after surgery. Conclusions MaR1 exerts distinct anti-inflammatory and pro-resolving effects through regulation of macrophage infiltration, NF-κB signalling, and cytokine release after surgery. Future studies on the use of pro-resolving lipid mediators may inform novel approaches to treat neuroinflammation and postoperative neurocognitive disorders.

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“…В експериментальній роботі на мишах доведено негативний вплив ІЛ-6 на післяопераційну нейрокогнітивну функцію [9]. У людей похилого віку високі рівні ІЛ-6 і низькі ІЛ-2 у періопераційному періоді асоціюються з великим ризиком розвитку післяопераційного делірію [10,11].…”

Section: вступunclassified

Study of the cytokine profile at surgeries on the lumbar spine: influence of the method of anesthesia

Lyzogub¹,

Leontyeva²,

Skidanov³

et al. 2018

ORTHOPAEDICS, TRAUMATOLOGY and PROSTHETICS

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1 ДУ «Інститут патології хребта та суглобів ім. проф. М. І. Ситенка НАМН України», Харків 2 КУ «Ровенська обласна клінічна лікарня». Україна Хирургические вмешательства на поясничном отделе поз воночника выполняют в условиях и общей, и спинальной анестезии (СА). Доказано, что любая операция сопровож дается высвобождением цитокинов, однако влияние на этот процесс метода анестезии не уточнено. Цель: исследовать концентрацию интерлейкина (ИЛ) 1β, 4 и 6 в сыворот ке крови пациентов во время операций на поясничном от деле позвоночника в условиях общей внутривенной или СА. Методы: обследовано 23 пациента (ASA III), которым выполнено хирургическое вмешательство на поясничном отделе позвоночника в условиях СА 0,5 % бупивакаином (n = 11) или общей пропофолфентаниловой анестезии (n = 12). Оценивали ИЛ1β, 4 и 6 до операции (Т1), через 30 мин (Т2), 3 ч (Т3) и 24 ч (Т4) после разреза. Контрольную группу (К) составили 11 здоровых людей. Результаты: кон центрация ИЛ1β в сыворотке крови на всех этапах наблю дения оказалась повышенной по сравнению со значениями контрольной группы (p < 0,01). Значимой разницы между группами и этапами исследования не выявлено. Уровень ИЛ6 в сыворотке крови у пациентов обеих групп был по вышен (p < 0,01). Во время операции (период Т2) у боль ных, получавших общую анестезию, отмечено достоверное увеличение концентрации ИЛ6 по сравнению с предопера ционным (p < 0,01) и Т2этапом группы СА (p < 0,01). Далее значимых различий не установлено. Концентрация ИЛ4 не отличалась от значения контрольной группы ни на од ном из этапов исследования. Выводы: дегенеративнодис трофические заболевания позвоночника сопровождаются повышением в сыворотке крови уровней провоспалительных цитокинов ИЛ1β и 6, которые остаются увеличенными ин траоперационно и в течение первых суток после операции. При общей анестезии через 30 мин после разреза наблю дается достоверно большая концентрация ИЛ6 по срав нению с группой СА. Ключевые слова: поясничный отдел позвоночника, хирургические вмешательства, анестезия, цитокины. © Лизогуб М. В., Леонтьєва Ф. С., Скіданов А. Г., Піонтковський В. К., 2018Surgical interventions on the lumbar spine are performed at both general and spinal anesthesia. It is proved that any sur gery is accompanied by the releasing of cytokines, but the effect of anesthesia on this process is not specified. Objective: to study the concentration of interleukin (IL) 1β, 4 and 6 in plasma pa tients during surgeries on lumbar spine at general intravenous or spinal anesthesia. Methods: we examined 23 patients (ASA I-II), operations on the lumar spine were performed at spinal anesthe sia with 0,5% bupivacaine (n=11) and general propofolfentanyl anesthesia (n=12). We assessed IL1β, 4 and 6 before surgery (T1), in 30 min (T2), in 3 hours (T3) and 24 hours (T4) after inci sion. Control group were healthy 11 people. Results: concentra tion of IL1β in plasma on all stages of study was increased com pare to control group (p < 0.01). Significant difference between groups and terms of study was not observed. The level of IL6 in ...

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

Abstract: 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.

Cited by 116 publications

References 32 publications

The Investigation of Hippocampus-Dependent Cognitive Decline Induced by Anesthesia/Surgery in Mice Through Integrated Behavioral Z-Scoring

The Investigation of Hippocampus-Dependent Cognitive Decline Induced by Anesthesia/Surgery in Mice Through Integrated Behavioral Z-Scoring

Maresin 1 attenuates neuroinflammation in a mouse model of perioperative neurocognitive disorders

Study of the cytokine profile at surgeries on the lumbar spine: influence of the method of anesthesia

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