Oxygen-sensitive outcomes and gene expression in acute ischemic stroke.
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.
Department of Surgery, The Ohio State University Medical Center, 473 W. 12th Avenue, Columbus, OH 43210, USA.
Cameron
C
Rink
Sashwati
S
Roy
Mahmood
M
Khan
Pavan
P
Ananth
Periannan
P
Kuppusamy
Chandan K
CK
Sen
Savita
S
Khanna
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D006931:Hyperbaric Oxygenation; D020244:Infarction, Middle Cerebral Artery; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000628:therapy
D015415:Biomarkers; D010100:Oxygen