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Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

ABSTRACT: 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.

SUBMITTER: Liu F

PROVIDER: S-EPMC4707202 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

Liu Fang F Rainosek Shuo W SW Frisch-Daiello Jessica L JL Patterson Tucker A TA Paule Merle G MG Slikker William W Wang Cheng C Han Xianlin X

Toxicological sciences : an official journal of the Society of Toxicology 20150723 2

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 a ...[more]

PMID: 26206149

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Project description:The safety of volatile anesthetics in infants and young children has been drawing increasing concern due to its potential neurotoxicity in the developing brain. Neuronal death is considered a major factor associated with developmental neurotoxicity after exposure to volatile anesthetics sevoflurane, but its mechanism remains elusive. Parthanatos, a new type of programmed cell death, resulting from poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation in response to DNA damage, was found to account for the pathogenesis of multiple neurological disorders. However, the role of Parthanatos in sevoflurane-induced neonatal neuronal cell death has not been investigated. To test it, neuronal cells treated with 2, 4, and 8% sevoflurane for 6, 12, and 24 h and postnatal day 7 rats exposed to 2.5% sevoflurane for 6 h were used in the present study. Our results found sevoflurane exposure induced neuronal cell death, which was accompanied by PARP-1 hyperactivation, cytoplasmic polymerized ADP-ribose (PAR) accumulation, mitochondrial depolarization, and apoptosis-inducing factor (AIF) nuclear translocation in the neuronal cells and hippocampi of rats. Pharmacological or genetic inhibition of PAPR-1 significantly alleviated sevoflurane-induced neuronal cell death and accumulation of PAR polymer and AIF nuclear translocation, which were consistent with the features of Parthanatos. We observed in vitro and in vivo that sevoflurane exposure resulted in DNA damage, given that 8-hydroxydeoxyguanosine (8-OHdG) and phosphorylation of histone variant H2AX (γH2AX) were improved. Moreover, we detected that sevoflurane exposure was associated with an overproduction of intracellular reactive oxygen species (ROS). Inhibition of ROS with antioxidant NAC markedly alleviated DNA damage caused by sevoflurane, indicating that ROS participated in the regulation of sevoflurane-induced DNA damage. Additionally, sevoflurane exposure resulted in upregulation of Parthanatos-related proteins and neuronal cell death, which were significantly attenuated by pretreatment with NAC. Therefore, these results suggest that sevoflurane exposure induces neuronal cell Parthanatos initiated by DNA damage in the developing brain via the increase of intracellular ROS.

Project description:BackgroundHypoxic-ischemic encephalopathy (HIE) has a high morbidity rate and involves severe neurologic deficits, including cerebral palsy. Therapeutic hypothermia (TH) has been shown to decrease the mortality rate and provide neuroprotection in infants with HIE. However, death and disability rates in HIE infants treated with TH remain high. Although the cellular mechanism of the neuroprotective effect of TH remains unclear, astrocytic erythropoietin (EPO) is known to be a key mediator of neuroprotection under hypoxic conditions. In the present study, we investigated the hypothermia effect on EPO expression in astrocytes and determined whether hypothermia attenuates neuronal damage via EPO signaling.MethodsAstrocytes derived from rat cerebral cortex were cultured under oxygen/glucose deprivation (OGD). The expression of EPO and hypoxia-inducible factor (HIF), a transcription factor of EPO, was assessed. After OGD, astrocytes were cultured under normothermic (37 °C) or hypothermic (33.5 °C) conditions, and then EPO and HIF expression was assessed. After OGD, rat cortical neurons were cultured in astrocyte-conditioned medium (ACM) derived from the hypothermic group, and neuronal apoptosis was evaluated.ResultsOGD induced EPO mRNA and protein expression, although at lower levels than hypoxia alone. HIF-1α and HIF-2α protein expression increased under hypoxia alone and OGD, although OGD increased HIF-2α protein expression less than hypoxia alone. EPO gene and protein expression after OGD was significantly higher under hypothermia. Moreover, expression of HIF-1α and HIF-2α protein was enhanced under hypothermia. In the presence of ACM derived from hypothermic astrocytes following OGD, the number of cleaved caspase 3 and TdT-mediated dUTP nick-end labeling-positive apoptotic neurons was lower than in the presence of ACM from normothermic astrocytes following OGD. Blockade of EPO signaling using anti-EPO neutralization antibody attenuated the anti-apoptotic effect of ACM derived from hypothermic astrocytes following OGD.ConclusionsHypothermia after OGD stabilized HIF-EPO signaling in astrocytes, and upregulated EPO expression could suppress neuronal apoptosis. Investigating the neuroprotective effect of EPO from astrocytes under hypothermic conditions may contribute to the development of novel neuroprotection-based therapies for HIE.

Dataset Information

Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

Publications

Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

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