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Updated: Mar 27, 2026
Two-vessel Occlusion Mouse Model of Cerebral Ischemia-reperfusion
Published on: March 1, 2019
Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia
O Z Chi1, S Barsoum1, N M Vega-Cotto2
1Dept. of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
Abstract:
Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1h and reperfusion for 2h with and without rapamycin (20mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5±0.8% control vs. 21.5±0.9% rapamycin). We also found that ischemia-reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia-reperfusion.
Insights
Inhibition of the mammalian target of rapamycin (mTOR) with rapamycin worsened oxygen balance and increased brain infarct size following cerebral ischemia-reperfusion injury in rats. This suggests mTOR plays a critical role in regulating oxygen homeostasis post-stroke.
Area of Science:
- Neuroscience
- Cardiovascular Science
- Cell Biology
Background:
- Mammalian target of rapamycin (mTOR) signaling pathways regulate cell growth and survival.
- Cerebral ischemia-reperfusion injury involves complex cellular responses impacting oxygen supply and consumption.
- Understanding mTOR's role in stroke is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the effect of mTOR inhibition on infarct size and microregional oxygen balance after cerebral ischemia-reperfusion.
- To determine if rapamycin alters oxygen supply/consumption dynamics in the ischemic brain.
Main Methods:
- Rats underwent middle cerebral artery occlusion for 1 hour followed by 2 hours of reperfusion.
- Rapamycin (20 mg/kg) was administered daily for two days prior to ischemia.
- Regional cerebral blood flow was measured using C(14)-iodoantipyrine autoradiography.
- Microregional oxygen saturations were assessed using microspectrophotometry.
Main Results:
- Rapamycin significantly increased cerebral oxygen consumption and worsened the oxygen supply/consumption balance in the reperfused cortex.
- Inhibition of mTOR with rapamycin led to a significant increase in cortical infarct size (21.5% vs. 13.5% in controls).
- Ischemia-reperfusion increased AKT and S6K1 phosphorylation, which was reduced by rapamycin.
Conclusions:
- mTOR plays a significant role in regulating oxygen balance following cerebral ischemia-reperfusion.
- Inhibition of mTOR exacerbates brain injury by impairing oxygen homeostasis.
- Targeting mTOR may be a critical factor in managing stroke outcomes.
