Isoflurane preconditioning is a phenomenon in which cells previously exposed to isoflurane exhibit protection against subsequent noxious stimuli. We hypothesize that isoflurane may cause subtle protein misfolding that persists at a sublethal level, stimulating cytoprotective mechanisms. Human neuroblastoma cells (SH-SY5Y) were exposed to isoflurane followed by quantitative analysis of the expression of several families of heat shock genes (84 total transcripts). Our data is consistent with a model of an early and delayed phase of preconditioning. Different patterns of expression of the 84 genes were seen at 1 and 24 h post-isoflurane exposure. Expression of 45 of the 84 genes were elevated at 1 h (or early phase) and remained upregulated at 24 h (or delayed phase). Subsets of the remaining genes were either unchanged (13 genes), early-specific upregulated (17 genes) or delayed-specific upregulated (9 genes). We also demonstrated that isoflurane caused a slight yet detectable misfold of a model protein. These data indicate that brief anesthetic exposure promotes specific patterns of gene expression, leading to preconditioning which would enhance the cell's ability to tolerate a future injury that involves protein misfolding. (C) 2011 Elsevier Inc. All rights reserved.