Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways
Abstract
It was shown recently that exposure of the developing rat brain during the peak of synaptogenesis to commonly used general anesthetics can trigger widespread apoptotic neurodegeneration in many regions of the developing rat brain and persistent learning/memory deficits later on in life. To understand the mechanism by which general anesthetics induce apoptotic neuronal death we studied two common apoptotic pathways--the intrinsic and the extrinsic pathway--at different time points during synaptogenesis. We found that the intrinsic pathway is activated early on during anesthesia exposure (within two hours), as measured by the down-regulation of bcl-x(L), up-regulation of cytochrome c and the activation of caspase-9 in 7-day-old rats (the peak of synaptogenesis), but remains inactivated in 14-day-old rats (the end of synaptogenesis). The extrinsic pathway is activated later on (within six hours of anesthesia exposure), as measured by the up-regulation of Fas protein and the activation of caspase-8 in 7-day-old rats, but remains inactivated in 14-day-old rats. Anesthesia-induced apoptotic neurodegeneration is age dependent with vulnerability closely correlating with the timing of synaptogenesis, i.e. the developing brain is most sensitive at the peak of synaptogenesis (7 days old) and least sensitive at the end of synaptogenesis (14 days old).
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Anesthetic-induced apoptosis is greatest if exposure occurs at P6-P7, with little or no increase in apoptosis at P14 in rodents.
“Studies about anesthetic-induced toxicity in brain development indicate that anesthetic-induced apoptosis is the greatest if exposure occurs at P6–P745611, with little or no increase in apoptosis at P1411 in rodents.”
From Transient blockade of ERK phosphorylation in the critical period causes autistic phenotypes as an adult in mice (2015) · cites this paper as [11]
There might be a critical period of vulnerability for exposure to anesthetics with peak at P6-P7 and the critical period would be closed before P14 in rodents.
“Thus, there might be a critical period of vulnerability for the exposure to anesthetics with the peak at P6–P7 and the critical period would be closed before P14 in rodents.”
From Transient blockade of ERK phosphorylation in the critical period causes autistic phenotypes as an adult in mice (2015) · cites this paper as [11]
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- Authors
- Yon, J.-H., Daniel-Johnson, J., Carter, L. B., & Jevtovic-Todorovic, V.
- Affiliations
- Inje University (KR)
- Virginia Commonwealth University (US)
- University of Virginia Health System (US)
- ORCID
- Yon, J.-H.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 135
- Issue
- 3
- Pages
- 815-827
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2054251296
- Cited by
- 467
- References
- 29
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 15 · 2023: 14 · 2022: 25 · 2021: 24 · 2020: 17 · 2019: 18 · 2018: 28 · 2017: 35 · 2016: 51 · 2015: 44 · 2014: 26 · 2013: 42 · 2012: 22
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k08da000406-06)
- National Institute on Aging (AG11355, P01AG011355)
- National Institute on Drug Abuse (K08 DA 00406)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- general anesthesia, neuronal apoptosis, synaptogenesis, developing brain, mitochondrial apoptosis, extrinsic apoptotic pathway, Bcl-xL, cytochrome c, caspase-9, Fas, caspase-8, learning and memory impairment
- MeSH terms
- Anesthesia, Animals, Blood Gas Analysis, Brain, Cerebrovascular Circulation, Enzyme Activation, Neurons, Nitrous Oxide, Blotting, Western, Signal Transduction, Cell Death, Laser-Doppler Flowmetry, Rats, Sprague-Dawley, Apoptosis, Anesthetics, Inhalation, fas Receptor, Caspases, Cytochromes c, bcl-X Protein, Rats
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