title: Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic-ischemic encephalopathy.
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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Armstrong
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jeong-Hoo
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Utpal
authors.initials: U
authors.lastname: Bhalala
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kulikowicz
authors.affiliation: 1] Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA [2] Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Reyes
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Moy
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Spicer
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Junchao
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009044:Motor Cortex / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D013552:Swine
chemical_list: D020169:Caspases