title: Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats.
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.
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Zhengqian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ni
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Chun
authors.initials: C
authors.lastname: Xia
authors.affiliation: Department of General Surgery, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Joey
authors.initials: J
authors.lastname: Jaw
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Mao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Guo
mesh_terms: D000375:Aging; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D019703:Calcineurin / Q000276:immunology*; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D007530:Isoflurane / Q000009:adverse effects*; D008297:Male; D008568:Memory / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D065853:Spatial Learning / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D016328:NF-kappa B; D007530:Isoflurane; D019703:Calcineurin