Improvement in Microregional Oxygen Supply/Consumption Balance and Infarct Size After Cerebral Ischemia-Reperfusion With Inhibition of p70 Ribosomal S6 Kinase (S6K1)

Background: We tested the hypothesis that inhibition of p70 ribosomal S6 kinase (S6K1) would decrease infarct size and improve microregional O₂ supply/consumption balance after cerebral ischemia-reperfusion. Methods: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 hour and reperfusion for 2 hours with or without PF-4708671 (S6K1 inhibitor, 75 mg/kg, 15 minutes after blockade). Regional cerebral blood flow was determined using a C¹⁴-iodoantipyrine autoradiographic technique. Regional small vessel (20-60 μm diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. Results: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O₂ consumption to the contralateral cortex. However, microregional O₂ supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O₂ saturation (23 of 80 veins with O₂ saturation below 45%). PF-4708671 did not significantly alter cerebral blood flow or O₂ consumption. However, it significantly reduced the number of small veins with low O₂ saturations in the reperfused region (6 of 80 veins with O₂ saturation below 45%). This was associated with a significantly reduced cortical infarct size after S6K1 inhibition (12.9 ±.8% control versus 6.6 ±.3% PF-4708671). Conclusion: This suggests that S6K1 inhibition is important for cell survival and that it reduces the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.