Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain.
BACKGROUND
Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of non-human primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathologic changes.


METHODS
With the same intensity of physiologic monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end-tidal Vol% (endotracheally intubated and mechanically ventilated) and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons.


RESULTS
Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0-48.2) apoptotic cells/mm of brain tissue in the isoflurane group and only 2.5 (range, 1.1-5.2) in the control group (difference significant at P = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions.


CONCLUSIONS
The developing non-human primate brain is sensitive to the apoptogenic action of isoflurane and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon 97239-3098, USA. brambrin@ohsu.edu
Ansgar M
AM
Brambrink
Alex S
AS
Evers
Michael S
MS
Avidan
Nuri B
NB
Farber
Derek J
DJ
Smith
Xuezhao
X
Zhang
Gregory A
GA
Dissen
Catherine E
CE
Creeley
John W
JW
Olney
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007442:Intubation, Intratracheal; D007530:Isoflurane / Q000633:toxicity*; D008253:Macaca mulatta; D009474:Neurons / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects / Q000648:ultrastructure
D018685:Anesthetics, Inhalation; D007530:Isoflurane; D053148:Caspase 3