Abstract
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.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
AIDS-Related Complex / genetics
-
AIDS-Related Complex / metabolism
-
Animals
-
Brain Ischemia / complications
-
Brain Ischemia / genetics*
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism
-
Cathepsin K
-
Cathepsins / genetics
-
Cathepsins / metabolism
-
Cdc20 Proteins
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cerebral Cortex / metabolism
-
Cerebral Cortex / pathology
-
Cerebral Cortex / physiopathology*
-
Cerebral Infarction / etiology
-
Cerebral Infarction / genetics*
-
Cortical Spreading Depression / drug effects
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Dizocilpine Maleate / pharmacology
-
Drug Interactions
-
Excitatory Amino Acid Antagonists / pharmacology
-
Fatty Acid-Binding Protein 7
-
Fatty Acid-Binding Proteins
-
Functional Laterality / genetics*
-
Functional Laterality / physiology
-
Gene Expression Profiling / methods
-
Gene Expression Regulation* / drug effects
-
HSP70 Heat-Shock Proteins / genetics
-
HSP70 Heat-Shock Proteins / metabolism
-
Immunohistochemistry / methods
-
Male
-
Nerve Tissue Proteins*
-
Nuclear Receptor Subfamily 4, Group A, Member 1
-
Oligonucleotide Array Sequence Analysis / methods
-
Phosphoric Monoester Hydrolases / genetics
-
Phosphoric Monoester Hydrolases / metabolism
-
Potassium Chloride / pharmacology
-
Proprotein Convertase 1 / genetics
-
Proprotein Convertase 1 / metabolism
-
RNA, Messenger / biosynthesis
-
Rats
-
Rats, Wistar
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Steroid
-
Reverse Transcriptase Polymerase Chain Reaction / methods
-
STAT3 Transcription Factor
-
Time Factors
-
Trans-Activators / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transcription, Genetic
-
Transcriptional Activation
Substances
-
Carrier Proteins
-
Cdc20 Proteins
-
Cdc20 protein, mouse
-
Cdc20 protein, rat
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
Excitatory Amino Acid Antagonists
-
Fabp7 protein, rat
-
Fatty Acid-Binding Protein 7
-
Fatty Acid-Binding Proteins
-
HSP70 Heat-Shock Proteins
-
Nerve Tissue Proteins
-
Nr4a1 protein, mouse
-
Nr4a1 protein, rat
-
Nuclear Receptor Subfamily 4, Group A, Member 1
-
RNA, Messenger
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Steroid
-
STAT3 Transcription Factor
-
Stat3 protein, rat
-
Trans-Activators
-
Transcription Factors
-
Potassium Chloride
-
Dizocilpine Maleate
-
Phosphoric Monoester Hydrolases
-
Cathepsins
-
Proprotein Convertase 1
-
Cathepsin K
-
Ctsk protein, mouse
-
Ctsk protein, rat