Preconditioning describes the ischemic stimulus that triggers an endogenous, 
neuroprotective response that protects the brain during a subsequent severe 
ischemic injury, a phenomenon known as 'tolerance'. Ischemic tolerance requires 
new protein synthesis, leads to genomic reprogramming of the brain's response to 
subsequent ischemia, and is transient. MicroRNAs (miRNAs) regulate 
posttranscriptional gene expression by exerting direct effects on messenger RNA 
(mRNA) translation. We examined miRNA expression in mouse cortex in response to 
preconditioning, ischemic injury, and tolerance. The results of our microarray 
analysis revealed that miRNA expression is consistently altered within each 
group, but that preconditioning was the foremost regulator of miRNAs. Our 
bioinformatic analysis results predicted that preconditioning-regulated miRNAs 
most prominently target mRNAs that encode transcriptional regulators; methyl-CpG 
binding protein 2 (MeCP2) was the most prominent target. No studies have linked 
MeCP2 to preconditioning or tolerance, yet miR-132, which regulates MeCP2 
expression, is decreased in preconditioned cortex. Downregulation of miR-132 is 
consistent with our finding that preconditioning ischemia induces a rapid 
increase in MeCP2 protein, but not mRNA, in mouse cortex. These studies reveal 
that ischemic preconditioning regulates expression of miRNAs and their predicted 
targets in mouse brain cortex, and further suggest that miRNAs and MeCP2 could 
serve as effectors of ischemic preconditioning-induced tolerance.