title: Striatal neuroprotection from neonatal hypoxia-ischemia in piglets by antioxidant treatment with EUK-134 or edaravone.
abstract: Striatal neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI, striatal neurons develop oxidative stress and organelle disruption by 3-6 h of recovery and ischemic cytopathology over 6-24 h of recovery. We tested the hypothesis that early treatment with the antioxidants EUK-134 (a manganese-salen derivative that acts as a scavenger of superoxide, hydrogen peroxide, nitric oxide or NO and peroxynitrite) or edaravone (MCI-186, a scavenger of hydroxyl radical and NO) protects striatal neurons from HI. Anesthetized newborn piglets were subjected to 40 min of hypoxia and 7 min of airway occlusion. At 30 min after resuscitation, the piglets received vehicle, EUK-134 or edaravone. Drug treatment did not affect arterial blood pressure, blood gases, blood glucose or rectal temperature. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 12 ± 6% (±SD) of sham-operated control density. Treatment with EUK-134 increased viability to 41 ± 17%, and treatment with edaravone increased viability to 39 ± 19%. In the caudate nucleus, neuronal viability was increased from 54 ± 11% in the vehicle group to 78 ± 15% in the EUK-134 group and to 73 ± 13% in the edaravone group. Antioxidant drug treatment accelerated recovery from neurologic deficits and decreased oxidative and nitrative damage to nucleic acids. Treatment with EUK-134 reduced the HI-induced formation of protein carbonyl groups and tyrosine nitration at 3 h of recovery. We conclude that systemic administration of antioxidant agents by 30 min after resuscitation from HI can reduce oxidative stress and salvage neurons in the highly vulnerable striatum in a large-animal model of neonatal HI. Therefore, oxidative stress is an important mechanism for this injury, and antioxidant therapy is a rational, mechanism-based approach to neuroprotection in the newborn brain.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287-4961, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Ni
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Erin L
authors.initials: EL
authors.lastname: Carter
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D012459:Salicylates / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine
chemical_list: D000975:Antioxidants; C433928:EUK-134; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D012459:Salicylates; D000077553:Edaravone; D000983:Antipyrine