Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion.
Deep hypothermic circulatory arrest is often required for the repair of complex congenital cardiac defects in infants. However, deep hypothermic circulatory arrest induces neuroapoptosis associated with later development of neurocognitive abnormalities. Selective cerebral perfusion theoretically provides superior neural protection possibly through modifications in cerebral substrate oxidation and closely integrated glutamate cycling. We tested the hypothesis that selective cerebral perfusion modulates glucose utilization, and ameliorates abnormalities in glutamate flux, which occur in association with neuroapoptosis during deep hypothermic circulatory arrest. Eighteen infant male Yorkshire piglets were assigned randomly to two groups of seven (deep hypothermic circulatory arrest or deep hypothermic circulatory arrest with selective cerebral perfusion for 60 minutes at 18℃) and four control pigs without cardiopulmonary bypass support. Carbon-13-labeled glucose as a metabolic tracer was infused, and gas chromatography-mass spectrometry and nuclear magnetic resonance were used for metabolic analysis in the frontal cortex. Following 2.5 h of cerebral reperfusion, we observed similar cerebral adenosine triphosphate levels, absolute levels of lactate and citric acid cycle intermediates, and carbon-13 enrichment among three groups. However, deep hypothermic circulatory arrest induced significant abnormalities in glutamate cycling resulting in reduced glutamate/glutamine and elevated γ-aminobutyric acid/glutamate along with neuroapoptosis, which were all prevented by selective cerebral perfusion. The data suggest that selective cerebral perfusion prevents these modifications in glutamate/glutamine/γ-aminobutyric acid cycling and protects the cerebral cortex from apoptosis.
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA.
Masaki
M
Kajimoto
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA.
Dolena R
DR
Ledee
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA.|Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, WA, USA.
Aaron K
AK
Olson
Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratories, Richland, WA, USA.
Nancy G
NG
Isern
Department of Nutrition, Université de Montréal and Montreal Heart Institute, Montréal, QC, Canada.
Isabelle
I
Robillard-Frayne
Department of Nutrition, Université de Montréal and Montreal Heart Institute, Montréal, QC, Canada.
Christine
C
Des Rosiers
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA michael.portman@seattlechildrens.org.|Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, WA, USA.
Michael A
MA
Portman
D000818:Animals; D017209:Apoptosis; D002315:Cardiopulmonary Bypass; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007036:Hypothermia, Induced; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D015424:Reperfusion; D013552:Swine
D018698:Glutamic Acid; D005947:Glucose
Energy metabolism; apoptosis; glucose; glutamate; magnetic resonance spectroscopy; neurotransmitters; γ-aminobutyric acid