Inhalation Anesthesia-Induced Neuronal Damage and Gene Expression Changes in Developing Rat Brain

Abstract

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.

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

“…The cutoff at the p-value minimizes the possibility of false selections of genes with no change in expression; and then ranking the genes which meet the p-value cutoff by their fold-changes serves to generate a list of DEGs with minimal discrepancy when the microarray analysis is performed by other researchers using different microarray platforms (Shi et al, 2008). Since differences between groups are usually smaller for brain tissues (Liu et al, 2011(Liu et al, , 2012Shi et al, 2010), the previously used standard cut-off for fold-change was chosen to maximize the number of DEGs that could be identified. Second, more stringent criteria (fold-change greater than 2.0 and p-value less than .05) were adopted to identify a more specific and shorter list of DEGs for comparison of pathway analysis with those DEGs recognized by the 1.5-fold change criteria.…”

Application of Nonhuman Primate Models in the Studies of Pediatric Anesthesia Neurotoxicity

“…64 In animal models for anesthesia-induced developmental neurotoxicity, a range of measures have been designated to intensively monitor physiological parameters, including vital signs, blood oxygenation levels, and homeostasis, to assess if any alterations, including hypoxia or hypotension, occur during anesthetic exposure. 6,13,37 During anesthetic exposures, vital signs of neonatal monkeys can be continuously monitored including heart rate, respiratory rate, blood pressure, and rectal temperature. 16,60,65 The homeostatic status in the exposed neonatal monkeys can be evaluated by continuously monitoring physiological parameters, including hemoglobin oxygen saturation, end-expiration of carbon dioxide (CO 2 ) concentration, and blood glucose levels using venous blood gas analysis at intervals of 1 to 2 hours during anesthetic exposure.…”

Protective effect of extract of Bletilla striata on isoflurane induced neuronal injury by altering PI3K/Akt pathway

“…injury [15] and data of this study suggest that isoflurane induces neuronal injury in the negative control group compared to control group of rats. Several reports reveal exposure of isoflurane causes impairment of cognitive function depending up on hippocampus region of the brain [16].…”