title: Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets.
abstract: The severity of perinatal hypoxia-ischemia and the delay in initiating therapeutic hypothermia limit the efficacy of hypothermia. After hypoxia-ischemia in neonatal piglets, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to oxidative stress at 3 h of reoxygenation and to eventual neurodegeneration. We tested whether early administration of a 20-HETE synthesis inhibitor after reoxygenation augments neuroprotection with 3-hour delayed hypothermia. In two hypothermic groups, whole body cooling from 38.5 to 34°C was initiated 3 h after hypoxia-ischemia. Rewarming occurred from 20 to 24 h; then anesthesia was discontinued. One hypothermic group received a 20-HETE inhibitor at 5 min after reoxygenation. A sham-operated group and another hypoxia-ischemia group remained normothermic. At 10 days of recovery, resuscitated piglets with delayed hypothermia alone had significantly greater viable neuronal density in the putamen, caudate nucleus, sensorimotor cortex, CA3 hippocampus, and thalamus than did piglets with normothermic recovery, but the values remained less than those in the sham-operated group. In piglets administered the 20-HETE inhibitor before hypothermia, the density of viable neurons in the putamen, cortex and thalamus was significantly greater than in the group with hypothermia alone. Cytochrome P450 4A, which can synthesize 20-HETE, was expressed in piglet neurons in these regions. We conclude that early treatment with a 20-HETE inhibitor enhances the therapeutic benefit of delayed hypothermia in protecting neurons in brain regions known to be particularly vulnerable to hypoxia-ischemia in term newborns.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Md, USA.
authors.forename: Junchao
authors.initials: J
authors.lastname: Zhu
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Jeong-Hoo
authors.initials: JH
authors.lastname: Lee
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Armstrong
authors.forename: Ewa
authors.initials: E
authors.lastname: Kulikowicz
authors.forename: Utpal S
authors.initials: US
authors.lastname: Bhalala
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
mesh_terms: D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D004195:Disease Models, Animal; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000628:therapy*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013552:Swine
chemical_list: D000578:Amidines; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D018696:Neuroprotective Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A