DOI: 10.1016/j.ebiom.2019.04.048
Abstract
Exposure to anesthesia in the early developmental stage may harbor potential adverse effects on cognitive functions. This multidisciplinary study integrates findings from non-human primates, mice, and pediatric patients to illustrate the mechanistic pathways implicating disruptions in folate metabolism due to sevoflurane anesthesia, leading to myelination deficits via epigenetic regulation of ERMN. The work not only establishes a correlated decline in blood folate levels post-anesthesia but also posits potential therapeutic interventions, including folate supplementation and targeted gene therapy, to ameliorate cognitive impairments.
In a groundbreaking study recently published in EBioMedicine, researchers have discovered that the use of sevoflurane anesthesia in young organisms, including rhesus macaque monkeys, mice, and children, has been found to disrupt folate metabolism leading to compromised myelination in the developing brain. This critical finding sheds light on how early-life exposure to anesthesia may impair cognitive functions and puts forth innovative interventions for the potential rescue of these detrimental effects.
The study, conducted by an esteemed group of scientists from prestigious institutions in China and the USA, employed a series of advanced techniques including DNA and RNA sequencing and immunohistochemistry. The research delineated a comprehensive approach to understanding the molecular repercussions of sevoflurane anesthesia, specifically targeting how it affects the TYMS gene related to folate metabolism and the myelination process within the brain.
The Role of ERMN and Epigenetic Mechanisms
The researchers identified ERMN, a myelination-specific protein, as the primary target directly affected by the altered metabolic activity caused by anesthesia in both young rhesus macaques and mice. The downregulation of the TYMS gene following anesthesia, as observed in the study, pointed to a reduction in the synthesis of thymidylate—one of the building blocks of DNA. Because folate is crucial for the production of thymidylate, this diminished capacity spells out broader ramifications on normal myelination and, by extension, cognitive development.
Using genome-wide DNA methylation analysis, the team discovered that the epigenetic regulation of ERMN was significantly altered following exposure to sevoflurane. This means that beyond changes to the genetic code, the way genes are expressed and used by the organism was also affected—leading to long-term developmental consequences.
The Pediatric Implication
The practical implications of the research were substantiated through a corollary study which measured blood folate levels in children who had undergone anesthesia and surgery. The data aligned with the preclinical findings as it indicated a reduction in folate levels post-procedure, laying a foundation for concerns regarding pediatric anesthesia practices and the reinforcement for probing into safer alternatives or supplementary measures.
Therapeutic Interventions and Cognitive Rescue
However, it’s not all dire news, as the study illuminates hope in the form of potential interventions. Systematic administration of folic acid and the expression of ERMN could not only counterbalance the myelination defects but also improve the associated cognitive deficits in mice models. The brain-specific delivery of the adeno-associated virus harboring ERMN expression illustrated a viable gene therapy strategy that holds promise for future clinical applications.
This comprehensive work represents a considerable leap in the understanding of anesthesia’s impact on young, developing brains and signals a vital area of medical research requiring immediate and sustained attention. The study emphasizes the indispensable role of folate in early cognitive development and how disturbances in its metabolism could underpin profound neurological sequelae.
References
1. Zhang L., Xue Z., Liu Q., et al. (2019). Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN. EBioMedicine, 43, 473-486. DOI: 10.1016/j.ebiom.2019.04.048
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3. Flick R.P., Katusic S.K., Colligan R.C., et al. (2011). Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics, 128(5), e1053-e1061. DOI: 10.1542/peds.2011-0351
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Keywords
1. Anesthesia Cognitive Impairment
2. Folate Metabolism Myelination
3. Pediatric Anesthesia Risks
4. ERMN Epigenetic Regulation
5. Sevoflurane Neurotoxicity