Electron Paramagnetic Resonance-Guided Normobaric Hyperoxia Treatment Protects the Brain by Maintaining Penumbral Oxygenation in a Rat Model of Transient Focal Cerebral Ischemia

Abstract

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 (pO2), can monitor penumbral changes of pO2. 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 O2 given during ischemia was able to maintain penumbral interstitial pO2 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.

Normobaric Hyperoxia Delays Perfusion/Diffusion Mismatch Evolution, Reduces Infarct Volume, and Differentially Affects Neuronal Cell Death Pathways after Suture Middle Cerebral Artery Occlusion in Rats

“…Normobaric hyperoxia treatment appeared to induce such apoptotic pathways in nonischemic brain tissue, corroborating previous studies that showed hyperoxia-induced cell death through caspase-3 activation (Gerstner et al, 2006;Lee and Choi, 2003). In light of decreased penumbral caspase-8 cleavage with NBO (Liu et al, 2006), it can be speculated that treatment with NBO only delays initiation of early stages of apoptosis but ultimately cannot prevent cell death (Wang and Lenardo, 2000). Potentially, reactive oxygen speciesmediated mitochondrial damage could lead to caspase-9 activation, leading to cell death through effector caspases such as caspase-6 (Gerstner et al, 2006;Lee and Choi, 2003;Wang and Lenardo, 2000); however, further studies are necessary to confirm these hypotheses.…”

Effects of Hyperoxia on Brain Tissue Oxygen Tension in Non-Sedated, Non- Anesthetized Arctic Ground Squirrels: An Animal Model of Hyperoxic Stress

“…Similar changes in brain tissue oxygenation during hyperoxic exposures have been reported in non-hibernating animals (Shin et al, 2007;Liu et al, 2006;Rossi et al, 2000;Shinozuka et al, 1989) and humans (Hlatky et al, 2008;Longhi et al, 2002;Macey et al, 2007;Tolias et al, 2004;Menzel et al, 1999) under anesthetic conditions using different O 2 measurement methods. Our P t O 2 results demonstrate that hibernating species share some of the same response mechanisms as non-hibernating species, like the rat, during hyperoxic exposure.…”

“…Despite the benefit of hyperoxia to increase tissue oxygen delivery to brain (Shin et al, 2007), hyperoxic ventilation can accentuate the effects of ischemia (Macey et al, 2007) and lead to oxidative stress and free radical damage (Liu et al, 2006). Paradoxically, hyperoxia results in increased ventilation, leading to hypocapnia, diminished cerebral blood flow and hindered oxygen delivery.…”

Dynamic Functional Cerebral Blood Volume Responses to Normobaric Hyperoxia in Acute Ischemic Stroke

“…Rodent studies using laser speckle flowmetry (Shin et al, 2007) showed that post-ischemic NBO caused an immediate increase in oxyhemoglobin concentration in the ischemic core, and improved cerebral blood flow (CBF) in the ipsilesional cortex. A study using electron paramagnetic resonance oximetry to measure interstitial oxygen tension (pO 2 ; Liu et al, 2006) found that NBO significantly increased pO 2 in the penumbra but not in the core. These results suggest that NBO's hemodynamic effects partly result from the shunting of blood from healthy to perfusiondeprived but still viable 'penumbral' brain tissue (i.e., reverse-steal or 'Robin Hood' effect; Lassen and Palvolgyi (1968)), possibly due to improved neurovascular coupling (Dirnagl, 1997;Shin et al, 2006) in penumbral regions.…”