title: 20-Hydroxyeicosatetraenoic Acid Inhibition by HET0016 Offers Neuroprotection, Decreases Edema, and Increases Cortical Cerebral Blood Flow in a Pediatric Asphyxial Cardiac Arrest Model in Rats.
abstract: Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jafar Sadik B
authors.initials: JS
authors.lastname: Shaik
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Alexander
authors.affiliation: Department of Internal Medicine, Department of Psychiatry, and Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Tudorascu
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Robert Sb
authors.initials: RS
authors.lastname: Clark
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Mioara D
authors.initials: MD
authors.lastname: Manole
mesh_terms: D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D001238:Asphyxia Neonatorum / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D001834:Body Water / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D002540:Cerebral Cortex / Q000098:blood supply* / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D006323:Heart Arrest / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors*; D008297:Male; D019636:Neurodegenerative Diseases / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D015777:Eicosanoids; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D018696:Neuroprotective Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System