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: Xinli Ni, Zeng-Jin Yang, Erin L Carter, Lee J Martin, Raymond C Koehler
• Journal: Developmental neuroscience (Dev Neurosci) Vol. 33 Issue 3-4 Pg. 299-311 ( 2011) ISSN: 1421-9859 [Electronic] Switzerland
• PMID: 21701140 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 S. Karger AG, Basel.

Chemical References

• Antioxidants
• EUK-134
• Free Radical Scavengers
• Neuroprotective Agents
• Organometallic Compounds
• Salicylates
• Edaravone
• Antipyrine

Topics

• Animals
• Animals, Newborn
• Antioxidants (pharmacology, therapeutic use)
• Antipyrine (analogs & derivatives, pharmacology, therapeutic use)
• Corpus Striatum (drug effects, pathology)
• Edaravone
• Free Radical Scavengers (pharmacology, therapeutic use)
• Hypoxia-Ischemia, Brain (drug therapy, pathology, physiopathology)
• Nerve Degeneration (drug therapy, pathology, physiopathology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Organometallic Compounds (pharmacology, therapeutic use)
• Oxidative Stress (drug effects)
• Salicylates (pharmacology, therapeutic use)
• Swine