title: Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia.
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.
authors.affiliation: Dept. of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: O Z
authors.initials: OZ
authors.lastname: Chi
authors.affiliation: Dept. of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: S
authors.initials: S
authors.lastname: Barsoum
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: N M
authors.initials: NM
authors.lastname: Vega-Cotto
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: E
authors.initials: E
authors.lastname: Jacinto
authors.affiliation: Dept. of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Dept. of Anesthesiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: S J
authors.initials: SJ
authors.lastname: Mellender
authors.affiliation: Dept. of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States. Electronic address: hweiss@rutgers.edu.
authors.forename: H R
authors.initials: HR
authors.lastname: Weiss
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D000983:Antipyrine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002247:Carbon Isotopes; D007166:Immunosuppressive Agents; D051058:Oncogene Protein v-akt; D000983:Antipyrine; C008135:iodoantipyrine; D020123:Sirolimus
keywords: cerebral blood flow; cerebral ischemia–reperfusion; mammalian target of rapamycin; oxygen supply/consumption; rapamycin