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.

Isoflurane‑induced postoperative cognitive dysfunction is mediated by hypoxia‑inducible factor‑1α‑dependent neuroinflammation in aged rats

“…The commonly used inhalation anesthetic isoflurane has been shown to induce activation of nuclear factor (NF)-κB, a master regulator of inflammation ( 8 ), increase TNF-α, IL-6 and IL-1β in the aged brain ( 9 ), and is associated with increased risk of cognitive dysfunction in the elderly. Hypoxia-inducible factor 1α (HIF-1α) is upregulated by factors such as angiotensinII ( 10 ) and carbachol ( 11 ), even though HIF-1α plays a major role in the maintenance of oxygen homeostasis and cellular adaptation ( 12 ).…”

Calmodulin‐dependent signalling pathways are activated and mediate the acute inflammatory response of injured skeletal muscle

“…; Li et al . ). Thus, next, we analysed the activities of CaMKII, CaMKIV and NFAT in damaged muscle.…”

Transcriptomic Response of Brain Tissue to Focused Ultrasound-Mediated Blood-Brain Barrier Disruption Depends Strongly on Anesthesia

“…Some examples include upregulation of T-cell associated markers Ly6a and Ctla2a, upregulation of adhesion markers Pecam1 and CD93, and downregulation of Nfkbia, the protein product of which inhibits NF-κB. Indeed, activation of NF-κB has been proposed as a mechanism by which volatile anesthetics elicit neuroinflammation [50,51]. Several rodent studies have demonstrated volatile anesthetics can also acutely induce expression of IL-6, IL-1β, and activated caspase-3 [52][53][54][55].…”