title: Effects of rapamycin pretreatment on blood-brain barrier disruption in cerebral ischemia-reperfusion.
abstract: The mammalian target of rapamycin (mTOR) pathway is essential in neuronal survival and repair in cerebral ischemia. Decreases in blood-brain barrier (BBB) disruption are associated with a decrease in neuronal damage in cerebral ischemia. This study was performed to investigate how pre-inhibition of the mTOR pathway with rapamycin would affect BBB disruption and the size of the infarcted cortical area in the early stage of focal cerebral ischemia-reperfusion using quantitative analysis of BBB disruption. Rats were treated with 20mg/kg of rapamycin i.p. once a day for 2days (Rapamycin Group) or vehicle (Control Group) before transient middle cerebral artery (MCA) occlusion. After one hour of MCA occlusion and two hours of reperfusion, the transfer coefficient (Ki) of (14)C-α-aminoisobutyric acid ((14)C-AIB) to measure the degree of BBB disruption and the size of the cortical infarct were determined. Ischemia-reperfusion increased the Ki in the Rapamycin treated (+15%) as well as in the untreated control group (+13%). However, rapamycin pretreatment moderately decreased Ki in the contralateral (-30%) as well as in the ischemic-reperfused (-29%) cortex when compared with the untreated control group. Rapamycin pretreatment substantially increased the percentage of cortical infarct compared with the control group (+56%). Our data suggest that activation of mTOR pathway is necessary for neuronal survival in the early stage of cerebral ischemia-perfusion and that the reason for the enlarged cortical infarct by rapamycin pretreatment may be related to its non-BBB effects on the mTOR pathway.
authors.affiliation: Department of Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Electronic address: chi@rwjms.rutgers.edu.
authors.forename: Oak Z
authors.initials: OZ
authors.lastname: Chi
authors.affiliation: Department of Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Mellender
authors.affiliation: Department of Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Sylviana
authors.initials: S
authors.lastname: Barsoum
authors.affiliation: Department of Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Damito
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D020520:Brain Infarction / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D008297:Male; D010539:Permeability; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: BBB permeability; Cerebral infarction; Cerebral ischemia-reperfusion; Neuroprotection; Rapamycin; mTOR