PMID- 26412317 OWN - NLM STAT- MEDLINE DCOM- 20160425 LR - 20200522 IS - 1097-685X (Electronic) IS - 0022-5223 (Print) IS - 0022-5223 (Linking) VI - 151 IP - 1 DP - 2016 Jan TI - Hypoxia diminishes the protective function of white-matter astrocytes in the developing brain. PG - 265-72.e1-3 LID - S0022-5223(15)01539-1 [pii] LID - 10.1016/j.jtcvs.2015.08.076 [doi] AB - OBJECTIVES: White-matter injury after surgery is common in neonates with cerebral immaturity secondary to in utero hypoxia. Astrocytes play a central role in brain protection; however, the reaction of astrocytes to hypothermic circulatory arrest (HCA) remains unknown. We investigated the role of astrocytes in white-matter injury after HCA and determined the effects of preoperative hypoxia on this role, using a novel mouse model. METHODS: Mice were exposed to hypoxia from days 3 to 11, which is equivalent to the third trimester in humans (prehypoxia, n = 49). Brain slices were transferred to a chamber perfused by cerebrospinal fluid. Oxygen-glucose deprivation (OGD) was performed to simulate ischemia-reperfusion/reoxygenation resulting from circulatory arrest under hypothermia. Astrocyte reactions were compared with preoperative normoxia (prenormoxia; n = 45). RESULTS: We observed astrocyte activation after 25 degrees C ischemia-reperfusion/reoxygenation in prenormoxia (P < .01). Astrocyte number after OGD correlated with caspase-3(+) cells (rho = .77, P = .001), confirming that astrogliosis is an important response after HCA. At 3 hours after OGD, astrocytes in prenormoxia had already proliferated and become activated (P < .05). Conversely, astrocytes that developed under hypoxia did not display these responses. At 20 hours after ischemia-reperfusion/reoxygenation, astrogliosis was not observed in prehypoxia, demonstrating that hypoxia altered the response of astrocytes to insult. In contrast to prenormoxia, caspase-3(+) cells in prehypoxia increased after ischemia reperfusion/reoxygenation, compared with control (P < .01). Caspase-3(+) cells were more common with prehypoxia than with prenormoxia (P < .001), suggesting that lack of astrogliosis permits increased white-matter injury. CONCLUSIONS: Preoperative hypoxia alters the neuroprotective function of astrocytes. Restoring this function before surgery may be a therapeutic option to reduce postoperative white-matter injury in the immature brain. CI - Copyright (c) 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved. FAU - Agematsu, Kota AU - Agematsu K AD - Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC. FAU - Korotcova, Ludmila AU - Korotcova L AD - Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC. FAU - Morton, Paul D AU - Morton PD AD - Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC. FAU - Gallo, Vittorio AU - Gallo V AD - Center for Neuroscience Research, Children's National Medical Center, Washington, DC. FAU - Jonas, Richard A AU - Jonas RA AD - Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC. FAU - Ishibashi, Nobuyuki AU - Ishibashi N AD - Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC. Electronic address: nishibas@childrensnational.org. LA - eng GR - R01NS045702/NS/NINDS NIH HHS/United States GR - U54 HD090257/HD/NICHD NIH HHS/United States GR - P30 HD040677/HD/NICHD NIH HHS/United States GR - R01 HL104173/HL/NHLBI NIH HHS/United States GR - R01 HL128546/HL/NHLBI NIH HHS/United States GR - R01 NS045702/NS/NINDS NIH HHS/United States GR - R01HL128546/HL/NHLBI NIH HHS/United States GR - P30HD40677/HD/NICHD NIH HHS/United States GR - R01HL104173/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150926 PL - United States TA - J Thorac Cardiovasc Surg JT - The Journal of thoracic and cardiovascular surgery JID - 0376343 RN - 0 (Glial Fibrillary Acidic Protein) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 3.4.22.- (Casp3 protein, mouse) RN - EC 3.4.22.- (Caspase 3) SB - IM CIN - J Thorac Cardiovasc Surg. 2016 Jan;151(1):273-4. PMID: 26463653 MH - Animals MH - Animals, Newborn MH - Astrocytes/metabolism/*pathology MH - Caspase 3/metabolism MH - Cell Proliferation MH - Disease Models, Animal MH - Fetal Hypoxia/metabolism/*pathology MH - Glial Fibrillary Acidic Protein/genetics MH - Gliosis MH - Green Fluorescent Proteins/biosynthesis/genetics MH - Hypothermia, Induced MH - Hypoxia-Ischemia, Brain/metabolism/*pathology/prevention & control MH - In Vitro Techniques MH - Leukoencephalopathies/metabolism/*pathology/prevention & control MH - Mice, Transgenic MH - Promoter Regions, Genetic MH - Reperfusion Injury/metabolism/*pathology/prevention & control MH - Time Factors MH - White Matter/growth & development/metabolism/*pathology PMC - PMC4690795 MID - NIHMS719442 OTO - NOTNLM OT - astrocyte OT - hypoxia OT - white matter COIS- No potential conflicts exists EDAT- 2015/09/29 06:00 MHDA- 2016/04/26 06:00 PMCR- 2017/01/01 CRDT- 2015/09/29 06:00 PHST- 2015/05/19 00:00 [received] PHST- 2015/08/17 00:00 [revised] PHST- 2015/08/23 00:00 [accepted] PHST- 2015/09/29 06:00 [entrez] PHST- 2015/09/29 06:00 [pubmed] PHST- 2016/04/26 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - S0022-5223(15)01539-1 [pii] AID - 10.1016/j.jtcvs.2015.08.076 [doi] PST - ppublish SO - J Thorac Cardiovasc Surg. 2016 Jan;151(1):265-72.e1-3. doi: 10.1016/j.jtcvs.2015.08.076. Epub 2015 Sep 26.