Isoflurane-induced Apoptosis of Neurons and Oligodendrocytes in the Fetal Rhesus Macaque Brain

Abstract

Background The authors have previously shown that exposure of the neonatal nonhuman primate (NHP) brain to isoflurane for 5 h causes widespread acute apoptotic degeneration of neurons and oligodendrocyte. The current study explored the potential apoptogenic action of isoflurane in the fetal NHP brain. Methods Fetal rhesus macaques at gestational age of 120 days (G120) were exposed in utero for 5 h to isoflurane anesthesia (n = 5) or to no anesthesia (control condition; n = 4), and all regions of the brain were systematically evaluated 3 h later for evidence of apoptotic degeneration of neurons or glia. Results Exposure of the G120 fetal NHP brain to isoflurane caused a significant increase in apoptosis of neurons and of oligodendrocytes at a stage when oligodendrocytes were just beginning to myelinate axons. The neuroapoptosis response was most prominent in the cerebellum, caudate, putamen, amygdala, and several cerebrocortical regions. Oligodendrocyte apoptosis was diffusely distributed over many white matter regions. The total number of apoptotic profiles (neurons + oligodendrocytes) in the isoflurane-exposed brains was increased 4.1-fold, compared with the brains from drug-naive controls. The total number of oligodendrocytes deleted by isoflurane was higher than the number of neurons deleted. Conclusions Isoflurane anesthesia for 5 h causes death of neurons and oligodendrocytes in the G120 fetal NHP brain. In the fetal brain, as the authors previously found in the neonatal NHP brain, oligodendrocytes become vulnerable when they are just achieving myelination competence. The neurotoxic potential of isoflurane increases between the third trimester (G120) and the neonatal period in the NHP brain.

Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains

“…Common general anesthetics such as ketamine and isoflurane have been reported to induce neuroapoptosis and cellular degeneration in actively developing brains in rodents (Hayashi et al, 2002;Ikonomidou et al, 1999;Jevtovic-Todorovic et al, 2003;Ma et al, 2007;Sanders et al, 2009Sanders et al, , 2010Scallet et al, 2004) and nonhuman primates (Creeley et al, 2013;Brambrink et al, 2012Brambrink et al, , 2010Slikker et al, 2007;Zou et al, 2009). Dexmedetomidine is a sedative and anesthetic with a different mechanism of action than ketamine and isoflurane.…”

“…It has been demonstrated that certain common anesthetic agents, such as ketamine and isofluorane, cause widespread apoptosis and neurodegeneration in neonatal rat (Hayashi et al, 2002;Ikonomidou et al, 1999;Jevtovic-Todorovic et al, 2003;Ma et al, 2007;Sanders et al, 2009Sanders et al, , 2010Scallet et al, 2004) and monkey (Creeley et al, 2013;Brambrink et al, 2012Brambrink et al, , 2010Slikker et al, 2007;Zou et al, 2009) brains. While ketamine and isoflurane have different pharmacologic actions in exerting their respective anesthetic effects (Brambrink et al, 2010;Haberny et al, 2002;Ma et al, 2007;Mellon et al, 2007), they both induce similar types of neuroapoptotic lesions and in similar locations in developing brains (Brambrink et al, 2010;Slikker et al, 2007;Zou et al, 2009).…”

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

“…Brains of both fetal [24] and neonatal rhesus macaques [8,11] display signs of neuronal apoptosis upon exposure to isoflurane (0.7 -1.5 Vol.% for 5 hours). In humans, there is epidemiological evidence to suggest a modestly elevated risk of adverse behavioural or developmental outcomes in children who were exposed to anaesthesia during early childhood [1,3,4].…”

“…Exposure to isoflurane, which affects various cell types outside and inside the brain [8,24], causes a panoply of cardiorespiratory and metabolic side effects [10]. Its use in newborn rodents is associated with considerable mortality [25].…”

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“…Se sabe que el desarrollo neurológico en animales se ve alterado con la administración de anestésicos generales aún por periodos cortos. Estudios preclínicos en fetos de roedores, cerdos y monos han mostrado que la exposición a anestésicos inhalatorios y drogas sedantes causa apoptosis neuronal 23,24 , exposición que también ha demostrado asociarse con trastornos del aprendizaje 25 . Este tema largamente debatido y que ha sido motivo de varias editoriales en revistas anestesiológicas 26,27,28 permanece aún siendo controversial.…”