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Neurochem.<\/jats:italic> (2012) <jats:bold>121<\/jats:bold>, 168\u2013179.<\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>20\u2010Hydroxyeicosatetraenoic acid (20\u2010HETE) is a cytochrome P450 metabolite of arachidonic acid that that contributes to infarct size following focal cerebral ischemia. However, little is known about the role of 20\u2010HETE in global cerebral ischemia or neonatal hypoxia\u2010ischemia (H\u2010I). The present study examined the effects of blockade of the synthesis of 20\u2010HETE with <jats:italic>N<\/jats:italic>\u2010hydroxy\u2010<jats:italic>N\u2032<\/jats:italic>\u2010(4\u2010<jats:italic>n<\/jats:italic>\u2010butyl\u20102\u2010methylphenyl) formamidine (HET0016) in neonatal piglets after H\u2010I to determine if it protects highly vulnerable striatal neurons. Administration of HET0016 after H\u2010I improved early neurological recovery and protected neurons in putamen after 4\u2003days of recovery. HET0016 had no significant effect on cerebral blood flow. cytochrome P450 4A immunoreactivity was detected in putamen neurons, and direct infusion of 20\u2010HETE in the putamen increased phosphorylation of Na<jats:sup>+<\/jats:sup>,K<jats:sup>+<\/jats:sup>\u2010ATPase and NMDA receptor NR1 subunit selectively at protein kinase C\u2010sensitive sites but not at protein kinase A\u2010sensitive sites. HET0016 selectively inhibited the H\u2010I induced phosphorylation at these same sites at 3\u2003h of recovery and improved Na<jats:sup>+<\/jats:sup>,K<jats:sup>+<\/jats:sup>\u2010ATPase activity. At 3\u2003h, HET0016 also suppressed H\u2010I induced extracellular signal\u2010regulated kinase 1\/2 activation and protein markers of nitrosative and oxidative stress. Thus, 20\u2010HETE can exert direct effects on key proteins involved in neuronal excitotoxicity <jats:italic>in vivo<\/jats:italic> and contributes to neurodegeneration after global cerebral ischemia in immature brain.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1471-4159.2012.07666.x","type":"journal-article","created":{"date-parts":[[2012,1,18]],"date-time":"2012-01-18T00:12:34Z","timestamp":1326845554000},"page":"168-179","source":"Crossref","is-referenced-by-count":40,"title":["Attenuation of neonatal ischemic brain damage using a 20\u2010HETE synthesis inhibitor"],"prefix":"10.1111","volume":"121","author":[{"given":"Zeng\u2010Jin","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin L.","family":"Carter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen K.","family":"Kibler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herman","family":"Kwansa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daina A.","family":"Crafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee J.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Roman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Harder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond C.","family":"Koehler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000072783.22373.FF"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00146.2009"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1128(200103)21:2<129::AID-MED1003>3.0.CO;2-H"},{"key":"e_1_2_7_5_1","first-page":"203","volume-title":"Subunit\u2010Specific NMDA Receptor Trafficking to Synapses","author":"Barria A","year":"2007"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199112000-00017"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.02203.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2005.03.004"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00003.2009"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(02)02272-5"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.6.C1981"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01172.2007"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.109.1.26"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00512.2008"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01416.2006"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1993.74.5.2585"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(01)00032-8"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.11.067"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(02)00285-1"},{"key":"e_1_2_7_20_1","first-page":"H2098","article-title":"Formation and action of a P\u2010450 4A metabolite of arachidonic acid in cat cerebral microvessels","volume":"266","author":"Harder D. 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