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General anesthesia disrupts infant brain development

The U.S. Food and Drug administration (FDA) has recently issued a safety advisory warning against exposure to anesthetics and sedatives during the third trimester of prenancy and the first three years of life. These medications can have lasting adverse effects on intellectual function of the developing baby.

New research published July 6 in the journal PLOS Biology by Eunchai Kang, David Mintz and colleagues based in The Johns Hopkins University School of Medicine, Baltimore, Maryland, find that early newborn mice pups exposed to isoflurane (a standard and widely used inhaled general anesthetic) have chronic and abnormal activation of their mTOR pathway, an intracellular signaling system critical to formation of normal brain development.
The research focused on the hippocampus, a brain region critical to learning and memory. The hippocampus contains a large number of neurons that develop in the postnatal period beginning immediately after birth and extending for about six weeks, and are therefore vulnerable to exposure from anesthesias.

15 day-old mice were exposed to doses of isoflurane with the drug's effect on the hippocampus being recorded. The structures of one class of neurons — the dentate gyrus granule cells — were found substantially changed. Specifically, branches or dendrites of these neurons were almost twice the length of those in untreated animals. This suggests the anesthetic caused abnormal acceleration in their growth.

In addition, researchers saw a significant reduction in the number of mature dendritic spines - the structures on dendrites where synapse exchanges occur.
To see whether these changes were associated with an effect on learning, treated and untreated mice were subjected to two standard behavioral tests (an object-place recognition test and a Y-maze test).

Isoflurane treated mice performed significantly worse in both tests.

The authors went on to show that pharmacologic inhibition of the mTOR pathway with the drug rapamycin protects mice from both abnormal structural changes in the brain and learning deficits associated with isoflurane exposure.

This study thereby links the adverse effects of early developmental anesthetic exposure with interruption of the mTOR pahtway. Such disruption has been previously implicated in numerous neurodevelopmental cognitive disorders including autism and Fragile-X mental retardation. This suggests a molecular mechanism by anesthetics might adversely effect brain development.
The FDA advisory warning is based on findings in both human and animal studies.

Some epidemiological research conducted in human populations reveals a correlation between exposure to anesthesia and worsened performance on school assessments, and deficits in neuropsychological testing. Though this is difficult to interpret as any exposure to general anesthesia implies an individual has had a prior medical condition and undergone surgery.

However, when epidemiological findings are considered along with mouse studies such as this one in which unequivocal exposure to anesthetics during key periods of brain development results in worsened performance on behavioral tests of learning and memory — a causal link in humans seems likely. The FDA safety advisory, therefore, specifically calls for further research to clarify risk to patients.

Suggested additional reading:
US Food and Drug Administration Drug Safety Communication: New warnings about using general anesthetics and sedation drugs in young children and pregnant women

The U.S. Food and Drug Administration (FDA) is warning that repeated or lengthy [3 hours or more] use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

The American Association of Nurse Anesthetists AANA:
Anesthesia Options for Labor and Delivery - What Every Expectant Mother Should Know

Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

Author summary
The United States Food and Drug Administration has recently warned that exposure to anesthetic and sedative drugs during the third trimester of prenatal development and during the first 3 years of life may Funding: Johns Hopkins ACCM Department anesthesiology.hopkinsmedicine.org (grant number StAAR) to CDM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH-NIGMS http://www.nih.gov (grant number 1R01GM120519-01 and 1K08GM104329-01) to CDM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH http://www.nih.gov (grant number NS048271 and MH105128) to GLM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH http://www.nih.gov (grant number NS047344) to HS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

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Jul 11, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

Exposure of early postnatal mice to the general anesthetic agent isoflurane, widely used
in surgery, has been shown to disrupt brain development and cause learning defects
in the intracellular mTOR Signaling Pathway"

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