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Updated: May 4, 2026
Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity AIDN: A Translational Neuroscience Approach
Published on: June 11, 2017
Propofol compared with isoflurane inhibits mitochondrial metabolism in immature swine cerebral cortex
Masaki Kajimoto1, Douglas B Atkinson1, Dolena R Ledee1
1Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA.
Insights
Propofol anesthesia impairs brain energy metabolism in piglets, disrupting the citric acid cycle and resembling a hypoxic state. These metabolic changes may contribute to propofol-induced neurotoxicity in developing brains.
Area of Science:
- Neuroscience
- Biochemistry
- Pediatric Anesthesiology
Background:
- Anesthetics like propofol are linked to neurocognitive disorders in children.
- Propofol's neurotoxic mechanisms, potentially energetic, require further investigation.
Purpose of the Study:
- To investigate the impact of propofol versus isoflurane on cerebral energy metabolism in immature swine.
- To elucidate the specific effects on citric acid cycle (CAC) substrate utilization in the developing brain.
Main Methods:
- Immature swine underwent 4-hour anesthesia with propofol or isoflurane.
- 13-Carbon-labeled glucose and leucine were infused to trace CAC metabolism in the parietal cortex.
- Systemic hemodynamics and cerebral oxygen saturation were monitored.
Main Results:
- Propofol, unlike isoflurane, depleted ATP and glycogen stores.
- Propofol reduced CAC intermediates (citrate, α-ketoglutarate) and mitochondrial complex II activity, while increasing succinate.
- Propofol inhibited pyruvate dehydrogenase, increased glycolysis, and caused lactate accumulation, mimicking hypoxia.
Conclusions:
- Propofol impairs CAC substrate flux in the immature brain, independent of systemic metabolic changes.
- These metabolic disruptions may underlie propofol's neurotoxicity in vulnerable young brains.
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.
