Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic-ischemic encephalopathy

Bing Wang, Jillian S. Armstrong, Jeong Hoo Lee, Utpal Bhalala, Ewa Kulikowicz, Hui Zhang, Michael Reyes, Nicole Moy, Dawn Spicer, Junchao Zhu, Zeng Jin Yang, Raymond C. Koehler, Lee J. Martin, Jennifer K. Lee

Research output: Contribution to journalArticle

Abstract

The consequences of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy are poorly understood. Adverse effects from suboptimal rewarming could diminish neuroprotection from hypothermia. Therefore, we tested whether rewarming is associated with apoptosis. Piglets underwent hypoxia-asphyxia followed by normothermic or hypothermic recovery at 2 hours. Hypothermic groups were divided into those with no rewarming, rewarming at 0.5 °C/hour, or rewarming at 4 °C/hour. Neurodegeneration at 29 hours was assessed by hematoxylin and eosin staining, TUNEL assay, and immunoblotting for cleaved caspase-3. Rewarmed piglets had more apoptosis in motor cortex than did those that remained hypothermic after hypoxia-asphyxia. Apoptosis in piriform cortex was greater in hypoxic-asphyxic, rewarmed piglets than in naive/sham piglets. Caspase-3 inhibitor suppressed apoptosis with rewarming. Rapidly rewarmed piglets had more caspase-3 cleavage in cerebral cortex than did piglets that remained hypothermic or piglets that were rewarmed slowly. We conclude that rewarming from therapeutic hypothermia can adversely affect the newborn brain by inducing apoptosis through caspase mechanisms.

Original languageEnglish (US)
Pages (from-to)781-793
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume35
Issue number5
DOIs
StatePublished - May 5 2015

Keywords

  • asphyxia
  • heart arrest
  • hypothermia
  • neuronal cell death
  • newborn
  • rewarming

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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