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 I kappa B-alpha and Stat3, and the beta-chemokine MIP-1 alpha (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.
Küry
Patrick
P
Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, D-40225, Düsseldorf, Germany.
Schroeter
Michael
M
Jander
Sebastian
S
D000386:AIDS-Related Complex / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000209:etiology / Q000235:genetics*; D013181:Cortical Spreading Depression / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007839:Functional Laterality / Q000235:genetics* / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009419:Nerve Tissue Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D002352:Carrier Proteins; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; C577494:Cdc20 protein, rat; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D010744:Phosphoric Monoester Hydrolases; D002403:Cathepsins; D045664:Proprotein Convertase 1; D056657:Cathepsin K; C534132:Ctsk protein, mouse; C534133:Ctsk protein, rat