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Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory
Andreas W Loepke1, George K Istaphanous, John J McAuliffe
1Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. andreas.loepke@cchmc.or
Insights
Neonatal exposure to isoflurane caused immediate brain cell degeneration in mice. However, long-term effects on neuronal density, motor activity, and memory were not observed, suggesting anesthesia safety in young patients.
Area of Science:
- Neuroscience
- Anesthesiology
- Developmental Biology
Background:
- Concerns exist regarding pediatric anesthesia safety due to potential neurodevelopmental effects of volatile anesthetics like isoflurane.
- Neonatal exposure to isoflurane, midazolam, and nitrous oxide has been linked to neurodegeneration and neurocognitive impairment in animal models.
- Hypoglycemia induced by isoflurane in neonatal mice was previously hypothesized as a cause for neurocognitive deficits.
Purpose of the Study:
- To investigate the impact of neonatal isoflurane exposure on brain cell viability, locomotor activity, and cognitive functions in mice.
- To determine if blood glucose levels mediate the neurotoxic effects of isoflurane in neonates.
- To assess the long-term consequences of early-life isoflurane exposure on neurological outcomes.
Main Methods:
- Neonatal mice were exposed to isoflurane or room air, with some receiving dextrose or saline injections.
- Arterial blood gases and glucose levels were measured post-exposure.
- Brain cell viability, spontaneous locomotor activity, and spatial learning/memory were assessed at various time points.
Main Results:
- Isoflurane exposure increased early apoptotic brain cell degeneration but did not alter adult neuronal density in key regions.
- Despite initial cell loss, adult mice showed no deficits in spontaneous locomotion, spatial learning, or memory.
- Neonatal isoflurane caused transient metabolic disturbances and increased mortality, but hypoglycemia was not responsible for neurodegeneration.
Conclusions:
- Neonatal isoflurane exposure induces acute brain cell degeneration in mice.
- No significant long-term neurocognitive or behavioral deficits were observed in adult mice following neonatal isoflurane exposure.
- These findings suggest that prolonged isoflurane exposure may not lead to lasting neurological impairments in this model.
Background:
Volatile anesthetics, such as isoflurane, are widely used in infants and neonates. Neurodegeneration and neurocognitive impairment after exposure to isoflurane, midazolam, and nitrous oxide in neonatal rats have raised concerns regarding the safety of pediatric anesthesia. In neonatal mice, prolonged isoflurane exposure triggers hypoglycemia, which could be responsible for the neurocognitive impairment. We examined the effects of neonatal isoflurane exposure and blood glucose on brain cell viability, spontaneous locomotor activity, as well as spatial learning and memory in mice.
Methods:
Seven-day-old mice were randomly assigned to 6 h of 1.5% isoflurane with or without injections of dextrose or normal saline, or to 6 h of room air without injections (no anesthesia). Arterial blood gases and glucose were measured. After 2 h, 18 h, or 11 wk postexposure, cellular viability was assessed in brain sections stained with Fluoro-Jade B, caspase 3, or NeuN. Nine weeks postexposure, spontaneous locomotor activity was assessed, and spatial learning and memory were evaluated in the Morris water maze using hidden and reduced platform trials.
Results:
Apoptotic cellular degeneration increased in several brain regions early after isoflurane exposure, compared with no anesthesia. Despite neonatal cell loss, however, adult neuronal density was unaltered in two brain regions significantly affected by the neonatal degeneration. In adulthood, spontaneous locomotor activity and spatial learning and memory performance were similar in all groups, regardless of neonatal isoflurane exposure. Neonatal isoflurane exposure led to an 18% mortality, and transiently increased Paco(2), lactate, and base deficit, and decreased blood glucose levels. However, hypoglycemia did not seem responsible for the neurodegeneration, as dextrose supplementation failed to prevent neuronal loss.
Conclusions:
Prolonged isoflurane exposure in neonatal mice led to increased immediate brain cell degeneration, however, no significant reductions in adult neuronal density or deficits in spontaneous locomotion, spatial learning, or memory function were observed.
