Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue.
In order to identify biological processes relevant for cell death and survival in the brain following stroke, the postischemic brain transcriptome was studied by a large-scale cDNA array analysis of three peri-infarct brain regions at eight time points during the first 24 h of reperfusion following middle cerebral artery occlusion in the rat. K-means cluster analysis revealed two distinct biphasic gene expression patterns that contained 44 genes (including 18 immediate early genes), involved in cell signaling and plasticity (i.e. MAP2K7, Sprouty2, Irs-2, Homer1, GPRC5B, Grasp). The first gene induction phase occurred at 0-3 h of reperfusion, and the second at 9-15 h, and was validated by in situ hybridization. Four gene clusters displayed a progressive increase in expression over time and included 50 genes linked to cell motility, lipid synthesis and trafficking (i.e. ApoD, NPC1, G3P-dehydrogenase1, and Choline kinase) or cell death-regulating genes such as mitochondrial CLIC. We conclude that a biphasic transcriptional up-regulation of the brain-derived neurotrophic factor (BDNF)-G-protein coupled receptor (GPCR)-mitogen-activated protein (MAP) kinase signaling pathways occurs in surviving tissue, concomitant with a progressive and persistent activation of cell proliferation signifying tissue regeneration, which provide the means for cell survival and postischemic brain plasticity.
Rickhag
Mattias
M
Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, University of Lund, Lund, Sweden.
Wieloch
Tadeusz
T
Gidö
Gunilla
G
Elmér
Eskil
E
Krogh
Morten
M
Murray
Joseph
J
Lohr
Scott
S
Bitter
Hans
H
Chin
Daniel J
DJ
von Schack
David
D
Shamloo
Mehrdad
M
Nikolich
Karoly
K
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000235:genetics*; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D017403:In Situ Hybridization; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000473:pathology; D008297:Male; D005810:Multigene Family / Q000235:genetics; D009416:Nerve Regeneration / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D015533:Transcriptional Activation
D018076:DNA, Complementary; D012313:RNA