title: n-3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling.
abstract: OBJECTIVE
  Omega-3 polyunsaturated fatty acids (n-3 PUFAs) attenuate neonatal hypoxic/ischemic (H/I) brain damage, but the underlying mechanisms are not fully understood. This study tested the hypothesis that n-3 PUFAs enhance Akt-dependent prosurvival signaling by promoting the biosynthesis of phosphatidylserine in neuronal cell membranes.
  
  
  METHODS
  Dietary n-3 PUFA supplementation was initiated on the second day of pregnancy in dams. H/I was induced in 7-day-old rat pups by ipsilateral common carotid artery occlusion followed by hypoxia (8% oxygen for 2.5 hours). Neurological outcomes, brain tissue loss, cell death, and the activation of signaling events were assessed after H/I. The effects of n-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) on oxygen-glucose deprivation-induced cell death and the underlying mechanism of protection were also examined in primary cortical neuron cultures.
  
  
  RESULTS
  n-3 PUFAs reduced brain tissue loss at 7 days after H/I and improved neurological outcomes, whereas inhibition of PI3K/Akt signaling by LY294002 partially abrogated this neuroprotective effect. Docosahexaenoic acid/eicosapentaenoic acid also prevented ischemic neuronal death through the Akt prosurvival pathway in vitro. Furthermore, docosahexaenoic acid/eicosapentaenoic acid increased the production of phosphatidylserine, the major membrane-bound phospholipids, after ischemia both in vitro and in vivo. A reduction in membrane phosphatidylserine by shRNA-mediated knockdown of phosphatidylserine synthetase-1 attenuated Akt activation and neuronal survival after docosahexaenoic acid/eicosapentaenoic acid treatment in the oxygen-glucose deprivation model.
  
  
  CONCLUSIONS
  n-3 PUFAs robustly protect against H/I-induced brain damage in neonates by activating Akt prosurvival pathway in compromised neurons. In addition, n-3 PUFAs promote the formation of membrane phosphatidylserine, thereby promoting Akt activity and improving cellular survival.
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.). chenj2@upmc.edu wtzhang@fudan.edu.cn.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: From the State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (W.Z., J.L., X.H., P.L., Y.G., J.C.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (X.H., J.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.). chenj2@upmc.edu wtzhang@fudan.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D010717:CDPdiacylglycerol-Serine O-Phosphatidyltransferase / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010718:Phosphatidylserines / Q000096:biosynthesis*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015525:Fatty Acids, Omega-3; D010718:Phosphatidylserines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D051057:Proto-Oncogene Proteins c-akt; D010717:CDPdiacylglycerol-Serine O-Phosphatidyltransferase
keywords: docosahexaenoic acids; eicosapentaenoic acid; neurons; omega-3 fatty acids; phosphatidylserine synthase