Isoflurane Exposure Induces Cell Death, Microglial Activation and Modifies the Expression of Genes Supporting Neurodevelopment and Cognitive Function in the Male Newborn Piglet Brain

Kevin D Broad, Jane Hassell, Bobbi Fleiss, Go Kawano, Mojgan Ezzati, Eridan Rocha-Ferreira, Mariya Hristova, Kate Bennett, Igor Fierens, Ryan Burnett, Badr Chaban, Daniel Alonso-Alconada, Aaron Oliver-Taylor, Ilias Tachsidis, Jamshid Rostami, Pierre Gressens, Robert D Sanders, Nicola J Robertson

Research output: Contribution to journalArticlepeer-review

Abstract

Exposure of the brain to general anesthesia during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex, incompletely understood and may be sexually dimorphic, but include developmentally inappropriate apoptosis, inflammation and a disruption to cognitively salient gene expression. We investigated the effects of a 6h isoflurane exposure on cell death, microglial activation and gene expression in the male neonatal piglet brain. Piglets (n = 6) were randomised to: (i) naive controls or (ii) 6h isoflurane. Cell death (TUNEL and caspase-3) and microglial activation were recorded in 7 brain regions. Changes in gene expression (microarray and qPCR) were assessed in the cingulate cortex. Electroencephalography (EEG) was recorded throughout. Isoflurane anesthesia induced significant increases in cell death in the cingulate and insular cortices, caudate nucleus, thalamus, putamen, internal capsule, periventricular white matter and hippocampus. Dying cells included both neurons and oligodendrocytes. Significantly, microglial activation was observed in the insula, pyriform, hippocampus, internal capsule, caudate and thalamus. Isoflurane induced significant disruption to the expression of 79 gene transcripts, of these 26 are important for the control of transcription and 23 are important for the mediation of neural plasticity, memory formation and recall. Our observations confirm that isoflurane increases apoptosis and inflammatory responses in the neonatal piglet brain but also suggests novel additional mechanisms by which isoflurane may induce adverse neural and cognitive development by disrupting the expression of genes mediating activity dependent development of neural circuits, the predictive adaptive responses of the brain, memory formation and recall.

Original languageEnglish
Pages (from-to)e0166784
JournalPLoS ONE
Volume11
Issue number11
DOIs
Publication statusPublished - 29 Nov 2016

Keywords

  • Anesthetics, General/pharmacology
  • Animals
  • Animals, Newborn
  • Brain/cytology
  • Cell Death/drug effects
  • Cognition/drug effects
  • Gene Expression Regulation, Developmental/drug effects
  • Gray Matter/cytology
  • Isoflurane/pharmacology
  • Male
  • Microglia/cytology
  • Swine
  • Time Factors
  • White Matter/cytology

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