Electron paramagnetic resonance-guided normobaric hyperoxia treatment protects the brain by maintaining penumbral oxygenation in a rat model of transient focal cerebral ischemia

Oxygen therapy for ischemic stroke remains controversial. Too much oxygen may lead to oxidative stress and free radical damage while too little oxygen will have minimal therapeutic effect. In vivo electron paramagnetic resonance (EPR) oximetry, which can measure localized interstitial partial oxygen (pO(2)), can monitor penumbral changes of pO(2). Therefore, we used EPR to study the effects of oxygen therapy in a rat model of 90-mins middle cerebral artery occlusion (MCAO). We found that 95% normobaric O-2, given during ischemia was able to maintain penumbral interstitial pO(2), levels close to the preischemic value while it may cause a two-fold increase in penumbral PO2 level if given during reperfusion. Elevation of the penumbra PO2 to preischemic physiologic level during MCAO significantly reduced infarction volume, improved neurologic function, decreased the generation of reactive oxygen species (ROS), and reduced matrix metalloproteinase (MMP)-9 expression and caspase-8 cleavage in the penumbra tissue of rats brain treated with oxygen. These results suggest that maintaining penumbral oxygenation by normobaric oxygen treatment during ischemia lead to neuroprotection, which is further reflected by the decreased production of ROS, MMP-9, and caspase-8.