Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states

Molecular mechanisms of neuroprotection that lead to ischaemic tolerance are incompletely understood. Identification of genes involved in the process would provide insight into cell survival and therapeutic approaches for stroke. We developed a mouse model of neuroprotection in stroke and did gene e...

Full description

Saved in:
Bibliographic Details
Published in:The Lancet (British edition) 2003-09, Vol.362 (9389), p.1028-1037
Main Authors: Stenzel-Poore, Mary P, Stevens, Susan L, Xiong, Zhigang, Lessov, Nikola S, Harrington, Christina A, Mori, Motomi, Meller, Robert, Rosenzweig, Holly L, Tobar, Eric, Shaw, Tatyana E, Chu, Xiangping, Simon, Roger P
Format: Article
Language:English
Subjects:
Animals
Bleeding Time
Blotting, Western
Brain - blood supply
Brain - pathology
Brain Ischemia - genetics
Brain Ischemia - physiopathology
Brain Ischemia - prevention & control
Cell Survival - genetics
Cell Survival - physiology
Cells, Cultured
Cerebrovascular Circulation - genetics
Cerebrovascular Circulation - physiology
Disease Models, Animal
Gene Expression - physiology
Genes
Hibernation - genetics
Hibernation - physiology
Humans
In Vitro Techniques
Ischemic Preconditioning - methods
Ischemic Preconditioning - standards
Medical treatment
Mice
Neuroprotective Agents - therapeutic use
Oligonucleotide Array Sequence Analysis
Polymerase Chain Reaction
Rats
Rats, Sprague-Dawley
Stroke
Stroke - pathology
Stroke - physiopathology
Stroke - therapy
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Molecular mechanisms of neuroprotection that lead to ischaemic tolerance are incompletely understood. Identification of genes involved in the process would provide insight into cell survival and therapeutic approaches for stroke. We developed a mouse model of neuroprotection in stroke and did gene expression profiling to identify potential neuroprotective genes and their associated pathways. Eight mice per condition were subjected to occlusion of the middle cerebral artery for 15 min (preconditioning), 60 min (injurious ischaemia), or preconditioning followed 72 h later by injurious ischaemia. RNA was extracted from the cortical regions of the ischaemic and non-ischaemic hemispheres. Three pools per condition were generated, and RNA was hybridised to oligonucleotide microarrays for comparison of ischaemic and non-ischaemic hemispheres. Real-time PCR and western blots were used to validate results. Follow-up experiments were done to address the biological relevance of findings. Microarray analysis revealed changes in gene expression with little overlap among the conditions of injurious ischaemia, ischaemic preconditioning, or both. Injurious ischaemia induced upregulation of gene expression; 49 (86%) of 57 genes regulated showed increased expression in the ischaemic hemisphere. By contrast, preconditioning followed by injurious ischaemia resulted in pronounced downregulation; 47 (77%) of 61 regulated genes showed lower expression. Preconditioning resulted in transcriptional changes involved in suppression of metabolic pathways and immune responses, reduction of ion-channel activity, and decreased blood coagulation. Preconditioning reprogrammes the response to ischaemic injury. Similar changes reported by others support an evolutionarily conserved endogenous response to decreased blood flow and oxygen limitation such as seen during hibernation.
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(03)14412-1