title: Isoflurane Exposure Induces Cell Death, Microglial Activation and Modifies the Expression of Genes Supporting Neurodevelopment and Cognitive Function in the Male Newborn Piglet Brain.
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.
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Broad
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Hassell
authors.affiliation: Centre for the Developing Brain, Kings College, St Thomas's Campus, London, United Kingdom.|Inserm, Paris, France.|University Paris Diderot, Sorbonne Paris Cite, Paris, France.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Go
authors.initials: G
authors.lastname: Kawano
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Ezzati
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Bennett
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Fierens
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Ryan
authors.initials: R
authors.lastname: Burnett
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Badr
authors.initials: B
authors.lastname: Chaban
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alonso-Alconada
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Aaron
authors.initials: A
authors.lastname: Oliver-Taylor
authors.affiliation: Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
authors.forename: Ilias
authors.initials: I
authors.lastname: Tachsidis
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Rostami
authors.affiliation: Centre for the Developing Brain, Kings College, St Thomas's Campus, London, United Kingdom.|Inserm, Paris, France.|University Paris Diderot, Sorbonne Paris Cite, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Department of Anesthesiology, University of Wisconsin, Madison, United States of America.|Wellcome Department of Imaging Neuroscience, University College London, London, United Kingdom.|Surgical Outcomes Research Centre, University College London Hospital, London, United Kingdom.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Nicola J
authors.identifier: http://orcid.org/0000-0002-5783-0828
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D018681:Anesthetics, General / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D066128:Gray Matter / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000166:cytology* / Q000187:drug effects*; D013552:Swine; D013997:Time Factors; D066127:White Matter / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000502:physiology
chemical_list: D018681:Anesthetics, General; D007530:Isoflurane