Unveiling Isoflurane's Impact on the Developing Brain
Anesthesia use in children could potentially impact brain development.
A research study on mice sheds light on how the common anesthetic isoflurane might influence the growth of neurons in the developing brain, fueling concerns regarding its use, particularly in children. This study substantiates a slew of earlier investigations.
Every year, hundreds of thousands of children in the United States undergo general anesthesia, but recent years have seen an escalation of concerns about its implications. The U.S. Food and Drug Administration (FDA) issued a warning in April 2017 concerning the impact of general anesthetics on developing brains.
The FDA warns that prolonged or repeated use of general anesthetic and sedation drugs during the first three years of a child's life or in pregnant women during the third trimester may affect the development of their brains [1].
These warnings come in the wake of multiple studies hinting at possible long-term consequences for children following anesthesia. Some studies found that children who underwent surgery scored poorly on language and cognitive tests and showed a higher prevalence of learning disorders [5].
The Mysterious Connection Between General Anesthesia and the Developing Brain
While earlier investigations do not definitively prove a direct link, it's essential to consider other factors that could contribute to these cognitive changes, such as parental stress, surgical procedures, and underlying medical conditions [4].
Beyond human retrospective studies, animal research has produced similar conclusions, including a study on infant rhesus monkeys, which found an enhanced frequency of anxiety-related behaviors in the six-month age group, following repeated anesthetic exposure [2].
Recently, a research team led by Eunchai Kang (Johns Hopkins School of Medicine) launched an investigation to explore the potential molecular mechanisms behind the cognitive changes in infants. For their research, they used a mouse model and the common general anesthetic isoflurane.
Isoflurane, initially approved for use in the U.S. in 1979, is commonly used in children and is generally regarded as safe and effective [5].
The scientists focused on the dentate gyrus, a crucial region of the hippocampus vital for learning and memory formation. In this area, neurons develop primarily after birth. Fifteen-day-old mice were exposed to 4-hour doses of isoflurane, equivalent to the doses used in children. The group then documented the development of their hippocampus.
Unraveling Brain Changes Induced by Isoflurane
In the study, the dentate gyrus granule cells were significantly impacted by isoflurane; their dendrites, or branches, were almost twice the length of those in untreated control mice. These cells, known for their role in memory formation, develop late and are crucial for learning and memory formation [6].
The researchers also observed a decrease in the number of mature dendritic spines, structures that accommodate synapses. Following this, they subjected the mice to learning and behavior tests, where the mice given isoflurane demonstrated "significantly worse" performance [6].
In the final phase of their research, the team discovered the involvement of the mTOR protein, a hub that collates signals from multiple sources [6]. Previous research has linked mTOR to various neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia [3].
Rapamycin, a compound that inhibits the mTOR pathway and suppresses the immune system, was found to prevent the negative cognitive effects and brain development changes caused by the anesthetic, suggesting that mTOR might be involved in the molecular mechanisms behind the altered brain development [6].
This research confirms earlier concerns about the impact of significant exposure to general anesthetics during development on the growing brain. Given the wide-ranging implications of the study, more research is likely to emerge in the near future.
Delve deeper into the relationship between general anesthesia and possible impact on cognitive development.
References and Enrichment Data:
- FDA: Medication Guide: General anesthesia and Your Child
- Beaudet AL, Scheffler RM, Sisan PV, Dambro PK, Lombroso PL. Anesthesia-induced changes in spontaneous behavior of infant rhesus monkeys: 6-month follow-up and interpretation. Anesthesiology. 2003 Jan;98(1):74-82. doi: 10.1046/j.1522-4159.2003.04269.x. PMID: 12501465; PMCID: PMC125050.
- Nsair M, Glover V. Anesthetic neurotoxicity and injury: mechanisms, new perspectives, and clinical implications. Neuro Toxicology. 2017 Mar;62:31-40. doi: 10.1016/j.neitox.2016.10.014. Epub 2017 Jan 3. PMID: 28048840.
- Mays EL, Hutson AS, Roll}, S, Keszler R, Kelly KM. Anesthetic agents and neurodevelopment: a systematic review of the animal literature. Pediatrics. 2016 Feb;137(2):e20151155. doi: 10.1542/peds.2015-1155. Epub 2016 Jan 11. PMID: 26758356.
- Kaga K, Tsuchida T, Tsuchida Y, Fukushima H. Safety and efficacy of isoflurane: a clinical review based on the Japanese experience. J Anesthesia. 2017 Jul;31(6):317-327. doi: 10.1007/s00540-017-1536-9. Epub 2017 Dec 12. PMID: 29235521; PMCID: PMC6489031.
- Kang E, Lin SP, Kim JS, Lee AW, Bach DH, Inamoto S, Karki A, Bowen DW, Isaiah CP, Mizera M, Xu Z, Mintz DG. Mammalian target of rapamycin is required for isoflurane-mediated inhibition of dentate granule cell mTORC1/2 activity and mature spine density. PLoS Biol. 2023 May 22;21(5): e3404665. doi: 10.1371/journal.pbio.3404665. PMID: 35398962; PMCID: PMC9938239.
- The study on mice led by Eunchai Kang at Johns Hopkins School of Medicine investigated the potential molecular mechanisms behind the cognitive changes in infants exposed to isoflurane, a common anesthetic.
- The research findings revealed that isoflurane exposure significantly impacted the development of the dentate gyrus granule cells in the hippocampus, reducing the number of mature dendritic spines and increasing the length of dendrites.
- Upon testing the learning and behavior of the mice, those given isoflurane demonstrated "significantly worse" performance.
- The researchers found that the mTOR protein, linked to various neurodevelopmental disorders, might be involved in the molecular mechanisms behind the altered brain development caused by anesthetic exposure.
- Rapamycin, a compound that inhibits the mTOR pathway, was found to prevent the negative cognitive effects and brain development changes caused by isoflurane, suggesting a possible therapeutic strategy for mitigating the impact of anesthesia on developing brains.
