Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

Li,Zhengqian; Ni,Cheng; Xia,Chun; Jaw,Joey; Wang,Yujie; Cao,Yiyun; Xu,Mao; Guo,Xiangyang

doi:10.3892/mmr.2016.5967

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

Authors:
- Zhengqian Li
- Cheng Ni
- Chun Xia
- Joey Jaw
- Yujie Wang
- Yiyun Cao
- Mao Xu
- Xiangyang Guo
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Affiliations: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China, Department of General Surgery, Peking University Third Hospital, Beijing 100191, P.R. China
Published online on: November 24, 2016 https://doi.org/10.3892/mmr.2016.5967
Pages: 201-209
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It is known that inhaled anesthetics induce neuroinflammation and facilitate postoperative cognitive dysfunction (POCD) in aged individuals; however, the mechanisms by which they mediate these effects remain elusive. Inhalation of the isoflurane anesthetic leads to opening of the mitochondrial permeability transition pore and loss of mitochondrial membrane potential. Therefore, mitochondrial retrograde signaling, which is an adaptive mechanism that facilitates the transmission of signals from dysfunctional mitochondria to the nucleus to activate target gene expression, may be activated during isoflurane inhalation. Therefore, the present study was designed to investigate the role of mitochondrial retrograde signaling in isoflurane-induced hippocampal neuroinflammation and cognitive impairment in aged rats. As calcineurin (CaN) serves an important role in the initiation of mitochondrial retrograde signaling, and nuclear factor-κB (NF‑κB) is involved in CaN signaling, their effects on isoflurane‑induced hippocampal neuroinflammation and cognitive impairment were investigated. Reactive oxygen species and mitochondrial membrane potential fluorescence staining, western blotting, colorimetric analysis, ELISA, immunofluorescence and the Morris water maze test were used in the present study. The results indicate that isoflurane induced hippocampal mitochondrial dysfunction and activated CaN, which subsequently lead to the putative activation of NF‑κB. These resulted in the elevation of interleukin‑1β (IL‑1β) expression (a typical marker of neuroinflammation), and was associated with cognitive impairment in aged rats. In addition, CaN and NF‑κB inhibition attenuated isoflurane-induced neuroinflammation and subsequent cognitive impairment. In conclusion, the results of the present study demonstrate the role of mitochondrial retrograde signaling and associated protein factors in inhaled anesthetic-induced neuroinflammation and cognitive impairment. These protein factors may therefore present promising therapeutic targets for the prevention of POCD.

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