Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9 h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage.
Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neuronal damage when exposure occurs during development. The precise mechanisms are not completely understood. To evaluate the degree of ketamine-induced neuronal toxicity, neural stem cells were isolated from gestational day 16 rat fetuses. On the eighth day in culture, proliferating neural stem cells were exposed for 24 h to ketamine at 1, 10, 100, and 500 μM. To determine the effect of ketamine on differentiated stem cells, separate cultures of neural stem cells were maintained in transition medium (DIV 6) for 1 day and kept in differentiation medium for another 3 days. Differentiated neural cells were exposed for 24 h to 10 μM ketamine. Markers of cellular proliferation and differentiation, mitochondrial health, cell death/damage, and oxidative damage were monitored to determine: (1) the effects of ketamine on neural stem cell proliferation and neural stem cell differentiation; (2) the nature and degree of ketamine-induced toxicity in proliferating neural stem cells and differentiated neural cells; and (3) to provide information regarding receptor expression and possible mechanisms underlying ketamine toxicity. After ketamine exposure at a clinically relevant concentration (10 μM), neural stem cell proliferation was not significantly affected and oxidative DNA damage was not induced. No significant effect on mitochondrial viability (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay) in neural stem cell cultures (growth medium) was observed at ketamine concentrations up to 500 μM. However, quantitative analysis shows that the number of differentiated neurons was substantially reduced in 10 μM ketamine-exposed cultures in differentiation medium, compared with the controls. No significant changes in the number of GFAP-positive astrocytes and O4-positive oligodendrocytes (in differentiation medium) were detected from ketamine-exposed cultures. The discussion focuses on: (1) the doses and time-course over which ketamine is associated with damage of neural cells; (2) how ketamine directs or signals neural stem cells/neural cells to undergo apoptosis or necrosis; (3) how functional neuronal transmitter receptors affect neurotoxicity induced by ketamine; and (4) advantages of using neural stem cell models to study critical issues related to ketamine anesthesia.
Nitrous Oxide (NO), an N-methyl-D-aspartate (NMDA) receptor antagonist, and isoflurane (ISO), which acts on multiple receptors including postsynaptic gamma-aminobutyric acid (GABA) receptors, are frequently used inhalation anesthetics, alone or as a part of a balanced anesthetic regimen administered to pregnant women and to human neonates and infants requiring surgery. The current study investigated histological features and gene expression profiles in response to prolonged exposure to NO or ISO alone, and their combination in developing rat brains. Postnatal day 7 rats were exposed to clinically-relevant concentrations of NO (70%), ISO (1.0%) or NO plus ISO (NO + ISO) for 6 hours. The neurotoxic effects were evaluated and the brain tissues were harvested for RNA extraction 6 hours after anesthetic administration. The prolonged exposure to NO + ISO produced elevated neuronal cell death as indicated by an increased number of TUNEL-positive cells in frontal cortical levels compared with control. No significant neurotoxic effects were observed in animals exposed to NO or ISO alone. DNA microarray analysis revealed gene expression changes after NO, ISO or NO + ISO exposure. Differentially expressed genes (DEGs) from the NO + ISO group were significantly associated with 45 pathways directly related to brain functions. Although the gene expression profiles from animals exposed to NO or ISO alone were remarkably different from those of the control group, the pathways of these genes involved were not closely associated with neurons. These findings provide novel insights into the mechanisms by which NO + ISO cause neurotoxicity in the developing brain, suggesting multiple factors are involved in the neuronal cell death-inducing effects (cascades) of NO + ISO.
Numerous studies have demonstrated that treatment with high dose anesthetics for a prolonged duration induces brain injury in infants. However, whether anesthetic treatment leading to neurotoxicity is associated with alterations in lipid metabolism and homeostasis is still unclear. This review first outlines the lipidomics tools for analysis of lipid molecular species that can inform alterations in lipid species after anesthetic exposure. Then the available data indicating anesthetics cause changes in lipid profiles in the brain and serum of infant monkeys in preclinical studies are summarized, and the potential mechanisms leading to the altered lipid metabolism and their association with anesthetic-induced brain injury are also discussed. Finally, whether lipid changes identified in serum of infant monkeys can serve as indicators for the early detection of anesthetic-induced brain injury is described. We believe extensive studies on alterations in lipids after exposure to anesthetics will allow us to better understand anesthetic-induced neurotoxicity, unravel its underlying biochemical mechanisms, and develop powerful biomarkers for early detection/monitoring of the toxicity.
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