Overcoming the dilemma of metabolic hypoxia following transient cerebral ischaemia. New insights from experimental hyperbaric oxygenation therapy

Improving tissue oxygenation in stroke is an important treatment strategy. Current clinical treatment options focus on early vessel recanalization to restore blood-flow to the ischemic tissue. Ischemic stimuli have been shown to induce a down regulation in mitochondrial respiratory chain activity in several tissues in the past. This effect was demonstrated for up to 72h and is described as “metabolic hypoxia“. Nitric oxide (NO) and oxygen have antagonistic effects on respiratory chain activity by acting in a competitive, dose dependent and reversible manner on complex IV. The increase of NO following ischemic stimuli could be responsible for this metabolic hypoxia, which augments the ischemic tissue damage.

We have recently shown that early hyperbaric oxygenation (HBO) reduces infarct volume and clinical outcome in experimental MCAO in rats. This effect was strong and long lasting and correlated well with changes in the spatial expression of markers of apoptosis, such as cleaved caspase-3.

In the present study, we addressed the question of how ischemia itself and HBO changed brain pO2 in a model of transient MCAO (90min.) followed by 90min of reperfusion. Brain pO2 was measured continuously by using a LICOX-probe in the infarct core or in sham-operated animals (control) by using a stereotactic frame. HBO treatment was performed in a pressure chamber with 100% O2, 3 atm/abs for 1h. Baseline pO2 was comparable in both groups (30,8mmHg±7,2mmHg [control] vs. 27,3mmHg±3,3mmHg). Following MCAO brain pO2 dropped immediately and remained at 5,3mmHg±3,5mmHg. Sham operation did not change brain pO2. However, reperfusion did not increase brain pO2 significantly. During HBO the MCAO group increased brain pO2 70mmHg±27mmHg vs. 386mmHg±197mmHg in controls. (All values are mean±SD)

The importance of the present study is that reperfusion itself did not increase brain pO2 in the infarct core. HBO, however, induced a 2,5-fold increase of brain pO2 in the infarct core, sufficient to promote cell survival. The lack of oxygen and the increase of NO following ischemia will end in a metabolic hypoxia by reducing the respiratory chain activity. The HBO-induced increase of brain pO2 might be the driving force to overcome reduced ATP-production by metabolic hypoxia.