Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets

Junchao Zhu, Bing Wang, Jeong Hoo Lee, Jillian S. Armstrong, Ewa Kulikowicz, Utpal S. Bhalala, Lee J Martin, Raymond C Koehler, Zeng Jin Yang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)376-389
Number of pages14
JournalDevelopmental Neuroscience
Volume37
Issue number4-5
DOIs
StatePublished - Jul 25 2015

Fingerprint

Induced Hypothermia
Hypothermia
Ischemia
Putamen
Thalamus
Neurons
Rewarming
Caudate Nucleus
Arachidonic Acid
Cytochrome P-450 Enzyme System
Hypoxia
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Neuroprotection
Hippocampus
Oxidative Stress
Anesthesia
Brain
Therapeutics

Keywords

  • 20-hydroxyeicosatetraenoic acid
  • Asphyxia
  • Cerebral ischemia
  • Cytochrome P450
  • Heart arrest
  • Hypoxic-ischemic encephalopathy
  • Neonate
  • Neuroprotection

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Neurology

Cite this

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets. / Zhu, Junchao; Wang, Bing; Lee, Jeong Hoo; Armstrong, Jillian S.; Kulikowicz, Ewa; Bhalala, Utpal S.; Martin, Lee J; Koehler, Raymond C; Yang, Zeng Jin.

In: Developmental Neuroscience, Vol. 37, No. 4-5, 25.07.2015, p. 376-389.

Research output: Contribution to journalArticle

Zhu, Junchao ; Wang, Bing ; Lee, Jeong Hoo ; Armstrong, Jillian S. ; Kulikowicz, Ewa ; Bhalala, Utpal S. ; Martin, Lee J ; Koehler, Raymond C ; Yang, Zeng Jin. / Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets. In: Developmental Neuroscience. 2015 ; Vol. 37, No. 4-5. pp. 376-389.
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