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Title: Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion

Abstract

Rationale: Deep hypothermic circulatory arrest (DHCA) is often required for the repair of complex congenital cardiac defects in infants. However, DHCA induces neuroapoptosis associated with later development of neurocognitive abnormalities. Selective cerebral perfusion (SCP) theoretically provides superior neural protection possibly through modifications in cerebral substrate oxidation and closely integrated glutamate cycling. Objectives: We tested the hypothesis that SCP modulates glucose entry into the citric acid cycle, and ameliorates abnormalities in glutamate flux which occur in association neuroapoptosis during DHCA. Methods and Results: Eighteen male Yorkshire piglets (age 34-44 days) were assigned randomly to 2 groups of 7 (DHCA or DHCA with SCP for 60 minutes at 18 °C) and 4 control pigs without cardiopulmonary bypass support. After the completion of rewarming from DHCA, 13-Carbon-labeled (13C) glucose as a metabolic tracer was infused. We used gas chromatography-mass spectrometry (GCMS) and nuclear magnetic resonance for metabolic analysis in the frontal cortex. Following 2.5 hours of cerebral reperfusion, we observed similar cerebral ATP levels, absolute levels of lactate and citric acid cycle intermediates, and 13C-enrichment. However, DHCA induced significant abnormalities in glutamate cycling resulting in reduced glutamate/glutamine and elevated γ-aminobutyric acid (GABA)/glutamate along with neuroapoptosis (TUNEL), which were all prevented by SCP. Conclusions:more » DHCA alone induces abnormalities in cycling of the major neurotransmitters in association with neuroapoptosis, but does not alter cerebral glucose utilization during reperfusion. The data suggest that SCP prevents these modifications in glutamate/glutamine/GABA cycling and protects the cerebral cortex from neuroapoptosis.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1406812
Report Number(s):
PNNL-SA-118083
Journal ID: ISSN 0271-678X; 49065; 48606; KP1704020
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Cerebral Blood Flow and Metabolism; Journal Volume: 36; Journal Issue: 11
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory

Citation Formats

Kajimoto, Masaki, Ledee, Dolena R., Olson, Aaron K., Isern, Nancy G., Robillard-Frayne, Isabelle, Des Rosiers, Christine, and Portman, Michael A. Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion. United States: N. p., 2016. Web. doi:10.1177/0271678X16666846.
Kajimoto, Masaki, Ledee, Dolena R., Olson, Aaron K., Isern, Nancy G., Robillard-Frayne, Isabelle, Des Rosiers, Christine, & Portman, Michael A. Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion. United States. doi:10.1177/0271678X16666846.
Kajimoto, Masaki, Ledee, Dolena R., Olson, Aaron K., Isern, Nancy G., Robillard-Frayne, Isabelle, Des Rosiers, Christine, and Portman, Michael A. Sat . "Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion". United States. doi:10.1177/0271678X16666846.
@article{osti_1406812,
title = {Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion},
author = {Kajimoto, Masaki and Ledee, Dolena R. and Olson, Aaron K. and Isern, Nancy G. and Robillard-Frayne, Isabelle and Des Rosiers, Christine and Portman, Michael A.},
abstractNote = {Rationale: Deep hypothermic circulatory arrest (DHCA) is often required for the repair of complex congenital cardiac defects in infants. However, DHCA induces neuroapoptosis associated with later development of neurocognitive abnormalities. Selective cerebral perfusion (SCP) theoretically provides superior neural protection possibly through modifications in cerebral substrate oxidation and closely integrated glutamate cycling. Objectives: We tested the hypothesis that SCP modulates glucose entry into the citric acid cycle, and ameliorates abnormalities in glutamate flux which occur in association neuroapoptosis during DHCA. Methods and Results: Eighteen male Yorkshire piglets (age 34-44 days) were assigned randomly to 2 groups of 7 (DHCA or DHCA with SCP for 60 minutes at 18 °C) and 4 control pigs without cardiopulmonary bypass support. After the completion of rewarming from DHCA, 13-Carbon-labeled (13C) glucose as a metabolic tracer was infused. We used gas chromatography-mass spectrometry (GCMS) and nuclear magnetic resonance for metabolic analysis in the frontal cortex. Following 2.5 hours of cerebral reperfusion, we observed similar cerebral ATP levels, absolute levels of lactate and citric acid cycle intermediates, and 13C-enrichment. However, DHCA induced significant abnormalities in glutamate cycling resulting in reduced glutamate/glutamine and elevated γ-aminobutyric acid (GABA)/glutamate along with neuroapoptosis (TUNEL), which were all prevented by SCP. Conclusions: DHCA alone induces abnormalities in cycling of the major neurotransmitters in association with neuroapoptosis, but does not alter cerebral glucose utilization during reperfusion. The data suggest that SCP prevents these modifications in glutamate/glutamine/GABA cycling and protects the cerebral cortex from neuroapoptosis.},
doi = {10.1177/0271678X16666846},
journal = {Journal of Cerebral Blood Flow and Metabolism},
number = 11,
volume = 36,
place = {United States},
year = {Sat Oct 01 00:00:00 EDT 2016},
month = {Sat Oct 01 00:00:00 EDT 2016}
}