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Published on: June 11, 2017
Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain
Ansgar M Brambrink1, Stephen A Back, Art Riddle
1Departments of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239-3098, USA. brambrin@ohsu.edu
Objective:
Previously we reported that exposure of 6-day-old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust neuroapoptosis response in developing brain. We have also observed (unpublished data) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane.
Methods:
Neonatal (P6) rhesus macaques were exposed for 5 hours to isoflurane anesthesia according to current clinical standards in pediatric anesthesia. Brains were collected 3 hours later and examined immunohistochemically to analyze apoptotic neuronal and glial death.
Results:
Brains exposed to isoflurane displayed significant apoptosis in both the white and gray matter throughout the central nervous system. Approximately 52% of the dying cells were glia, and 48% were neurons. Oligodendrocytes (OLs) engaged in myelinogenesis were selectively vulnerable, in contrast to OL progenitors, astrocytes, microglia, and interstitial neurons. When adjusted for control rates of OL apoptosis, the percentage of OLs that degenerated in the forebrain white matter of the isoflurane-treated group was 6.3% of the total population of myelinating OLs.
Interpretation:
Exposure of the infant rhesus macaque brain to isoflurane for 5 hours is sufficient to cause widespread apoptosis of neurons and OLs throughout the developing brain. Deletion of OLs at a stage when they are just beginning to myelinate axons could potentially have adverse long-term neurobehavioral consequences that might be additive to the potential consequences of isoflurane-induced neuroapoptosis.
Insights
Anesthesia with isoflurane in infant macaques caused widespread brain cell death, particularly affecting myelinating oligodendrocytes (OLs). This significant loss of OLs during development may lead to long-term neurobehavioral issues.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Anesthesiology
Background:
- Neonatal anesthesia is crucial but carries potential risks for developing brains.
- Previous research indicated isoflurane exposure causes neuroapoptosis in infant brains.
- Apoptotic cellular profiles resembling glia were observed in white matter following isoflurane exposure.
Purpose of the Study:
- To identify the cellular types undergoing apoptosis in the white matter after isoflurane exposure.
- To quantify the extent of glial cell death in the developing brain following anesthesia.
Main Methods:
- Neonatal rhesus macaques (postnatal day 6) received a 5-hour exposure to isoflurane anesthesia.
- Brain tissue was collected 3 hours post-exposure for immunohistochemical analysis.
- Apoptotic neuronal and glial cell death was assessed throughout the central nervous system.
Main Results:
- Isoflurane exposure resulted in significant apoptosis in both white and gray matter.
- Approximately 52% of apoptotic cells identified were glia, and 48% were neurons.
- Myelinating oligodendrocytes (OLs) were selectively vulnerable, with 6.3% of forebrain OLs undergoing apoptosis.
Conclusions:
- A 5-hour isoflurane exposure induces widespread neuronal and oligodendrocyte apoptosis in the infant rhesus macaque brain.
- Selective deletion of myelinating OLs during a critical developmental window may have long-term neurobehavioral consequences.
- These consequences could be additive to other potential effects of isoflurane-induced neuroapoptosis.
