Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non-ischemic cortex

Focal brain infarcts are surrounded by extended perilesional zones that comprise the partially ischemic penumbra but also completely non‐ischemic cortex of the remote ipsilateral hemisphere. To delineate the impact of lesion‐associated vs. remote processes on transcriptional programming after focal ischemia, we used cDNA array analysis, quantitative real‐time polymerase chain reaction and immunohistochemistry in the photothrombosis model of circumscribed cortical ischemia in rats. At an early stage of 4 h after ischemia, gene induction occurred to a similar extent in the ischemic infarct and remote non‐ischemic cortex of the ipsilateral hemisphere. Among the genes induced in non‐ischemic cortex we found the NGF‐inducible genes PC3, VGF and Arc, the transcriptional regulators IκB‐α and Stat3, and the β‐chemokine MIP‐1α (CCL3). At 3 days, the spatial pattern of gene expression had changed dramatically with brain fatty acid‐binding protein as the only gene significantly induced in non‐ischemic ipsilateral cortex. In contrast, numerous genes were exclusively regulated at the lesion site, comprising genes involved in cell cycle regulation, proteolysis, apoptosis, lipid homeostasis and anti‐inflammatory counter‐regulation. Cortical spreading depression was identified as the main mechanism underlying gene induction in remote non‐ischemic cortex. Our data demonstrate a dynamic spatiotemporal pattern of gene induction, which may contribute to delayed progression of damage or, alternatively, mediate neuroprotection, tissue remodeling and functional compensation.