Interstitial pO₂ in Ischemic Penumbra and Core are Differentially Affected following Transient Focal Cerebral Ischemia in Rats

Abstract

Summary:Stroke causes heterogeneous changes in tissue oxygenation, with a region of decreased blood flow, the penumbra, surrounding a severely damaged ischemic core. Treatment of acute ischemic stroke aims to save this penumbra before its irreversible damage by continued ischemia. However, effective treatment remains elusive due to incomplete understanding of processes leading to penumbral death. While oxygenation is central in ischemic neuronal death, it is unclear exactly what actual changes occur in interstitial oxygen tension (pO 2 ) in ischemic regions during stroke, particularly the penumbra. Using the unique capability of in vivo electron paramagnetic resonance (EPR) oximetry to measure localized interstitial pO 2 , we measured both absolute values, and temporal changes of pO 2 in ischemic penumbra and core during ischemia and reperfusion in a rat model. Ischemia rapidly decreased interstitial pO 2 to 32% ± 7.6% and 4% ± 0.6% of pre-ischemic values in penumbra and core, respectively 1 hour after ischemia. Importantly, whilst reperfusion restored core pO 2 close to its pre-ischemic value, penumbral pO 2 only partially recovered. Hyperoxic treatment significantly increased penumbral pO 2 during ischemia, but not in the core, and also increased penumbral pO 2 during reperfusion. These divergent, important changes in pO 2 in penumbra and core were explained by combined differences in cellular oxygen consumption rates and microcirculation conditions. We therefore demonstrate that interstitial pO 2 in penumbra and core is differentially affected during ischemia and reperfusion, providing new insights to the pathophysiology of stroke. The results support normobaric hyperoxia as a potential early intervention to save penumbral tissue in acute ischemic stroke.

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

“…Aside from improving tissue oxygen delivery to areas of diminished blood flow (Liu et al, 2004), it has been suggested that oxygen may partially be neuroprotective by inducing cerebral vasoconstriction in normal brain tissue, with subsequent decreases in intracranial pressure and/or an inverse steal of blood into the mismatch area (Nighoghossian and Trouillas, 1997). However, no significant changes in CBF were observed in this study, corroborating previous studies that showed unchanged cerebral perfusion during or shortly after oxygen treatment in models of focal cerebral ischemia (Henninger et al, 2006a).…”

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

“…[20][21][22][23] Confirmation of 23,31 Of note, although this paper focuses on longitudinal WM changes, it will be of interest to determine differences, if any, between WM compared with graymatter pO 2 in the SHR/SP model using EPR oximetry in future endeavors. We measured pO 2 in the WM of SHR/SP at 6 weeks of age before the onset of severe hypertension; all of the animals in the three groups showed similar levels of pO 2 up to 12 weeks.…”

“…Electron paramagnetic resonance oximetry measurements obtained at 6 to 8 weeks were consistent with pO 2 values obtained from WKY rats and the literature. [21][22][23] At 9 weeks of age, a gradual increase in WM pO 2 was observed that continued to rise weekly up to 12 weeks of age. At age week 12, a significant 32% increase in pO 2 in the WM of SHR/SP rats was observed compared with baseline measurements at age weeks 6 to 8 as shown in Figure 3A.…”

“…The peak-to-peak linewidth of the spectrum was obtained via computer linefitting, and converted to pO 2 values according to a calibration curve for the oximetry probe LiPc as previously described. [21][22][23] Electron paramagnetic resonance acquisition parameters: microwave power of 18 mW, a microwave frequency of 1.07 GHz, a center magnetic field strength of 380 G, a scan range of 1.0 G, and a modulation amplitude of less than one-third of the White-matter tissue oxygen in SHR/SP rats J Weaver et al intrinsic EPR linewidth. Interstitial pO 2 was measured continuously throughout the study and reported at the time points shown.…”

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

“…Our present findings demonstrating reduced hippocampal protein tyrosine nitration and retention of PDHC enzyme activity with normoxic resuscitation support the need for additional preclinical and clinical studies to resolve this issue. The concept that hyperoxia worsens oxidative tissue damage and neurologic outcome after acute brain injury may not, however, apply to other forms of injury, e.g., stroke and trauma, as evidence suggests that hyperoxia can under some circumstances be beneficial [73][74][75][76][77]. The time during which the brain is exposed to high O 2 can also determine whether hyperoxia is helpful or detrimental.…”