147680 - commentary rapalink 1 increased infarct size.pdf (132.38 kB)
Commentary: Rapalink-1 increased infarct size in early cerebral ischemia–reperfusion with increased blood–brain barrier disruption
journal contributionposted on 2023-05-21, 04:01 authored by Beard, DJ, Hadley, G, Brad SutherlandBrad Sutherland, Buchan, AM
It has been reported that the mechanistic target of rapamycin (mTOR) pathway is involved in cerebral ischemiaâ€“reperfusion injury. One of the important pathological changes during reperfusion after cerebral ischemia is disruption of bloodâ€“brain barrier (BBB). Rapamycin, a first-generation mTOR inhibitor, produces divergent effects on neuronal survival and alteration in BBB disruption. In this study, we investigated how Rapalink-1, a third-generation mTOR inhibitor, would affect neuronal survival and BBB disruption in the very early stage of cerebral ischemiaâ€“reperfusion that is within the time window of thrombolysis therapy. The middle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. Of note, 2 mg/kg of Rapalink-1 or vehicle was administered intraperitoneally 10 min after MCAO. After 1 h of MCAO and 2 h of reperfusion, the transfer coefficient (Ki) of 14C-Î±-aminoisobutyric acid (104 Da) and the volume of 3H-dextran (70,000 Da) distribution were determined to assess the degree of BBB disruption. At the same time points, phosphorylated S6 (Ser240/244) and Akt (Ser473) as well as matrix metalloproteinase-2 (MMP2) protein level were determined by Western blot along with the infarct size using tetrazolium stain. Rapalink-1 increased the Ki in the ischemic-reperfused cortex (IR-C, +23%, p < 0.05) without a significant change in the volume of dextran distribution. Rapalink-1 increased the percentage of cortical infarct out of the total cortical area (+41%, p < 0.005). Rapalink-1 significantly decreased phosphorylated S6 and Akt to half the level of the control rats in the IR-C, which suggests that both of the mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2) were inhibited. The MMP2 level was increased suggesting that BBB disruption could be aggravated by Rapalink-1. Taken together, our data suggest that inhibiting both mTORC1 and mTORC2 by Rapalink-1 could worsen the neuronal damage in the early stage of cerebral ischemiaâ€“reperfusion and that the aggravation of BBB disruption could be one of the contributing factors.
National Health & Medical Research Council
Publication titleFrontiers in Physiology
Department/SchoolTasmanian School of Medicine
PublisherFrontiers Research Foundation
Place of publicationSwitzerland
Rights statementCopyright © 2021 Beard, Hadley, Sutherland and Buchan. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License (https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.