Identification of novel modulators of ischemic neuronal death helps in developing new strategies to prevent the stroke-induced neurological dysfunction. Hence, the present study evaluated the gene expression changes in rat cerebral cortex at 6 and 24 h of reperfusion following transient middle cerebral artery occlusion (MCAO) by GeneChip analysis. Transient MCAO resulted in selective increased mRNA levels of genes involved in stress, inflammation, transcription and plasticity, and decreased mRNA levels of genes which control neurotransmitter function and ionic balance. In addition to a number of established ischemia-related genes, many genes not previously implicated in transient focal ischemia-induced brain damage [suppressor of cytokine signaling (SOCS)-3, cAMP responsive element modulator (CREM), cytosolic retinol binding protein (CRBP), silencer factor-B, survival motor neuron (SMN), interferon-gamma regulatory factor-1 (IRF-1), galanin, neurotrimin, proteasome subunit RC8, synaptosomal-associated protein (SNAP)-25 A and B, synapsin 1a, neurexin 1-beta, ras-related rab3, vesicular GABA transporter (VGAT), digoxin carrier protein, neuronal calcium sensor-1 and neurodap] were observed to be altered in the ischemic cortex. Real-time PCR confirmed the GeneChip results for several of these transcripts. SOCS-3 is a gene up-regulated after ischemia which modulates inflammation by controlling cytokine levels. Antisense knockdown of ischemia-induced SOCS-3 protein expression exacerbated transient MCAO-induced infarct volume assigning a neuroprotective role to SOCS-3, a gene not heretofore implicated in ischemic neuronal damage.