Oxygen-sensitive outcomes and gene expression in acute ischemic stroke

J Cereb Blood Flow Metab. 2010 Jul;30(7):1275-87. doi: 10.1038/jcbfm.2010.7. Epub 2010 Feb 10.

Abstract

Acute ischemic stroke (AIS) results in focal deprivation of blood-borne factors, one of them being oxygen. The purpose of this study was two-fold: (1) to identify therapeutic conditions for supplemental oxygen in AIS and (2) to use transcriptome-wide screening toward uncovering oxygen-sensitive mechanisms. Transient MCAO in rodents was used to delineate the therapeutic potential of normobaric (NBO, 100% O(2), 1ATA) and hyperbaric oxygen (HBO, 100% O(2), 2ATA) during ischemia (iNBO, iHBO) and after reperfusion (rNBO, rHBO). Stroke lesion was quantified using 4.7 T MRI at 48 h. Supplemental oxygen during AIS significantly attenuated percent stroke hemisphere lesion volume as compared with that in room air (RA) controls, whereas identical treatment immediately after reperfusion exacerbated lesion volume (RA=22.4+/-1.8, iNBO=9.9+/-3.6, iHBO=6.6+/-4.8, rNBO=29.8+/-3.6, rHBO=35.4+/-7.6). iNBO and iHBO corrected penumbra tissue pO(2) during AIS as measured by EPR oxymetry. Unbiased query of oxygen-sensitive transcriptome in stroke-affected tissue identified 5,769 differentially expressed genes. Candidate genes were verified by real-time PCR using neurons laser-captured from the stroke-affected somatosensory cortex. Directed microarray analysis showed that supplemental oxygen limited leukocyte accumulation to the infarct site by attenuation of stroke-inducible proinflammatory chemokine response. The findings provide key information relevant to understanding oxygen-dependent molecular mechanisms in the AIS-affected brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Brain Ischemia* / metabolism
  • Brain Ischemia* / pathology
  • Brain Ischemia* / therapy
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Humans
  • Hyperbaric Oxygenation*
  • Infarction, Middle Cerebral Artery
  • Leukocytes / cytology
  • Leukocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Oxidative Stress
  • Oxygen / metabolism*
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Stroke* / metabolism
  • Stroke* / pathology
  • Stroke* / therapy

Substances

  • Biomarkers
  • Oxygen