title: Propofol compared with isoflurane inhibits mitochondrial metabolism in immature swine cerebral cortex.
abstract: Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and α-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kajimoto
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Atkinson
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Dolena R
authors.initials: DR
authors.lastname: Ledee
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Ernst-Bernhard
authors.initials: EB
authors.lastname: Kayser
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Phil G
authors.initials: PG
authors.lastname: Morgan
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Sedensky
authors.affiliation: Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA.
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Isern
authors.affiliation: Department of Nutrition, Université de Montréal and Montreal Heart Institute, Montréal, Quebec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.affiliation: 1] Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA [2] Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
mesh_terms: D000280:Administration, Inhalation; D018681:Anesthetics, General / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D007262:Infusions, Intravenous; D007530:Isoflurane / Q000008:administration & dosage / Q000009:adverse effects*; D007930:Leucine / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000009:adverse effects*; D013552:Swine / Q000254:growth & development / Q000378:metabolism*
chemical_list: D018681:Anesthetics, General; D007530:Isoflurane; D007930:Leucine; D005947:Glucose; D015742:Propofol