Exposure to the anesthetic agent isoflurane increases "programmed cell death" of specific types of cells in the newborn mouse brain, reports a study in the April issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).
With prolonged exposure, a common inhaled anesthesia eliminates approximately two percent of neurons in the cortex of newborn mice. Although its relevance to anesthesia in human newborns remains to be determined, the study by Dr George K. Istaphanous and colleagues of Cincinnati Children's Hospital Medical Center provides unprecedented detail on the cellular-level effects of anesthetics on the developing brain.
Isoflurane Exposure Increases 'Programmed Death' of Brain Cells
In the study, seven-day-old mice were exposed to isoflurane for several hours. After exposure, sophisticated examinations were performed to assess the extent of isoflurane-induced brain cell death, including the specific types, locations, and functions of brain cells lost.
Isoflurane exposure led to widespread increases programmed cell death, called apoptosis, throughout the brain. Although cell loss was substantially higher after isoflurane exposure, the cell types lost were similar to the cells lost in the apoptosis that is part of normal brain maturation. In both cases, mainly neurons were lost. Neurons are the cells that transmit and store information.
The rate of cell death in the superficial cortex -- the thick outer layer of the brain -- was at least eleven times higher in isoflurane-exposed animals than seen with normal brain maturation. Overall, approximately two percent of cortical neurons were lost after isoflurane exposure. Astrocytes, another major type of cortical brain cells, were less affected by anesthetic exposure.
Relevance to Anesthesia in Human Newborns Is Unclear -- For Now
A growing body of evidence suggests that isoflurane and similar anesthetics may have toxic effects on brain cells in newborn animals and humans. "However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized," according to Dr Istaphanous and colleagues.
The new study provides detailed information on the extent and types of brain cell loss resulting from prolonged isoflurane exposure in newborn mice. It's unclear whether the two percent brain cell loss induced in the experiments would lead to any permanent damage -- in previous studies, newborn isoflurane-exposed mice showed no obvious brain damage long after the exposure.
It can't be assumed that isoflurane causes similar patterns of cellular damage in human newborns requiring general anesthesia, Dr Istaphanous and coauthors emphasize. Some studies have linked early-life exposure to anesthesia and surgery to later behavioral and learning abnormalities. Other studies have found no adverse affects on children exposed to anesthetics during vulnerable times of brain development. Further research on the selective nature and molecular mechanisms of isoflurane-induced brain cell death would be needed to determine the relevance of the experimental findings, if any, to human infants undergoing anesthesia.
- George K. Istaphanous, Christopher G. Ward, Xinyu Nan, Elizabeth A. Hughes, John C. McCann, John J. McAuliffe, Steve C. Danzer, Andreas W. Loepke. Characterization and Quantification of Isoflurane-Induced Developmental Apoptotic Cell Death in Mouse Cerebral Cortex. Anesthesia & Analgesia, 2013; 116 (4): 845 DOI: 10.1213/ANE.0b013e318281e988
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