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

Abstract

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.

• Authors: Harvey R Weiss, Scott J Mellender, Geza K Kiss, Xia Liu, Oak Z Chi
• Journal: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association (J Stroke Cerebrovasc Dis) Vol. 28 Issue 10 Pg. 104276 (Oct 2019) ISSN: 1532-8511 [Electronic] United States
• PMID: 31350168 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Neuroprotective Agents
• PF-4708671
• Piperazines
• Ribosomal Protein S6 Kinases
• Rps6kb1 protein, rat
• Oxygen

Topics

• Animals
• Brain (blood supply, drug effects, enzymology, pathology)
• Cerebrovascular Circulation (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Imidazoles (pharmacology)
• Infarction, Middle Cerebral Artery (drug therapy, enzymology, pathology, physiopathology)
• Male
• Microcirculation (drug effects)
• Neuroprotective Agents (pharmacology)
• Oxygen (blood)
• Oxygen Consumption (drug effects)
• Piperazines (pharmacology)
• Rats, Inbred F344
• Reperfusion Injury (enzymology, pathology, physiopathology, prevention & control)
• Ribosomal Protein S6 Kinases (antagonists & inhibitors, metabolism)