Although much recent evidence has demonstrated that neuroinflammation contributes to volatile anesthetic-induced cognitive deficits, there are few existing mechanistic explanations for this inflammatory process. This study was conducted to investigate the effects of the volatile anesthetic isoflurane on canonical nuclear factor (NF)-kappa B signaling, and to explore its association with hippocampal interleukin (IL)-1 beta levels and anesthetic-related cognitive changes in aged rats. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in I kappa B kinase and I kappa B phosphorylation, as well as a reduction in the NF-kappa B inhibitory protein (I kappa B alpha), were observed in the hippocampi of isoflurane-exposed rats compared with control rats. These events were accompanied by an increase in NF-kappa B p65 nuclear translocation at 6 h after isoflurane exposure and hippocampal IL-1 beta elevation from 1 to 6 h after isoflurane exposure. Nevertheless, no significant neuroglia activation was observed. Pharmacological inhibition of NF-kappa B activation by pyrrolidine dithiocarbamate markedly suppressed the IL-1 beta increase and NF-kappa B signaling, and also mitigated the severity of cognitive deficits in the Morris water maze task. Overall, our results demonstrate that isoflurane-induced cognitive deficits may stem from upregulation of hippocampal partially via activation of the canonical NF-kappa B pathway, in aged rats. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.