title: Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239, USA. poorem@ohsu.edu
authors.forename: Mary P
authors.initials: MP
authors.lastname: Stenzel-Poore
authors.forename: Susan L
authors.initials: SL
authors.lastname: Stevens
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xiong
authors.forename: Nikola S
authors.initials: NS
authors.lastname: Lessov
authors.forename: Christina A
authors.initials: CA
authors.lastname: Harrington
authors.forename: Motomi
authors.initials: M
authors.lastname: Mori
authors.forename: Robert
authors.initials: R
authors.lastname: Meller
authors.forename: Holly L
authors.initials: HL
authors.lastname: Rosenzweig
authors.forename: Eric
authors.initials: E
authors.lastname: Tobar
authors.forename: Tatyana E
authors.initials: TE
authors.lastname: Shaw
authors.forename: Xiangping
authors.initials: X
authors.lastname: Chu
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
mesh_terms: D000818:Animals; D001760:Bleeding Time; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology*; D006605:Hibernation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning / Q000379:methods* / Q000592:standards; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy
chemical_list: D018696:Neuroprotective Agents