PMID- 22178140 OWN - NLM STAT- MEDLINE DCOM- 20120426 LR - 20211203 IS - 1872-7972 (Electronic) IS - 0304-3940 (Print) IS - 0304-3940 (Linking) VI - 507 IP - 2 DP - 2012 Jan 24 TI - mTOR activates hypoxia-inducible factor-1alpha and inhibits neuronal apoptosis in the developing rat brain during the early phase after hypoxia-ischemia. PG - 118-23 LID - 10.1016/j.neulet.2011.11.058 [doi] AB - The mammalian target of rapamycin (mTOR) exerts neuroprotective effects under hypoxic or ischemic conditions. To explore whether mTOR participates in neuroprotective signaling through regulation of hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and neuronal apoptosis in developing rat brain with hypoxia-ischemia (HI), we operated on postnatal day 10 rats by ligating the common carotid artery followed by exposure to systemic hypoxia. Brains were collected at various intervals to detect the expression of mTOR, phosphorylated mTOR (p-mTOR), HIF-1alpha, VEGF and cleaved caspase 3 (CC3), using immunohistochemistry and Western blot analysis. We also used terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) to detect neuronal apoptosis. The p-mTOR protein expression increased at 2h after HI, peaked at 8h, lasted 24h, and then dropped to the basal level. Also, the expression of HIF-1alpha and VEGF was significantly enhanced and peaked at 8h after HI. Up-regulated expression of CC3 was observed at 2h, peaked at 24h, and lasted 72h after HI. Increased neuronal apoptosis is associated with reduced HIF-1alpha and VEGF expression. Furthermore, pretreatment with rapamycin, a mTOR specific inhibitor, significantly inhibited HIF-1alpha and VEGF protein after HI. The expression of CC3 and the number of TUNEL-positive cells were up-regulated at 8h and down-regulated at 24h after HI in the rapamycin-treated group. Our findings suggest that mTOR may participate in the regulation of HIF-1alpha, VEGF and neuronal apoptosis, serving neuroprotective functions after HI in developing rat brain. CI - Copyright (c) 2011 Elsevier Ireland Ltd. All rights reserved. FAU - Chen, Hongju AU - Chen H AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. FAU - Xiong, Tao AU - Xiong T FAU - Qu, Yi AU - Qu Y FAU - Zhao, Fengyan AU - Zhao F FAU - Ferriero, Donna AU - Ferriero D FAU - Mu, Dezhi AU - Mu D LA - eng GR - R01 NS033997/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20111208 PL - Ireland TA - Neurosci Lett JT - Neuroscience letters JID - 7600130 RN - 0 (Hif1a protein, rat) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Animals, Newborn MH - Apoptosis/*physiology MH - Blotting, Western MH - Brain/cytology/metabolism MH - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism MH - Hypoxia-Ischemia, Brain/*metabolism MH - Immunohistochemistry MH - In Situ Nick-End Labeling MH - Male MH - Neurons/cytology/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/physiology MH - TOR Serine-Threonine Kinases/*metabolism MH - Vascular Endothelial Growth Factor A/metabolism PMC - PMC3525671 MID - NIHMS427466 COIS- Conflict of interest statement All of the authors involved in preparation of the above manuscript declare no conflict of interest in any form. EDAT- 2011/12/20 06:00 MHDA- 2012/04/27 06:00 PMCR- 2012/12/18 CRDT- 2011/12/20 06:00 PHST- 2011/09/21 00:00 [received] PHST- 2011/11/12 00:00 [revised] PHST- 2011/11/29 00:00 [accepted] PHST- 2011/12/20 06:00 [entrez] PHST- 2011/12/20 06:00 [pubmed] PHST- 2012/04/27 06:00 [medline] PHST- 2012/12/18 00:00 [pmc-release] AID - S0304-3940(11)01580-1 [pii] AID - 10.1016/j.neulet.2011.11.058 [doi] PST - ppublish SO - Neurosci Lett. 2012 Jan 24;507(2):118-23. doi: 10.1016/j.neulet.2011.11.058. Epub 2011 Dec 8.