Abstract
Neonatal exposure to general anesthetics has been associated with neurotoxicity and morphologic changes in the developing brain. Isoflurane is a volatile anesthetic widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated the effects of a single neonatal isoflurane (3% in oxygen, 2 h) exposure in rats at postnatal day (PND) 7, in short-term (24 h — PND8) and long-term (adulthood) protocols. In PND8, ex vivo analysis of hippocampal and frontal cortex slices evaluated cell viability and susceptibility to in vitro glutamate challenge. In adult rats, behavioral parameters related to anxiety-like behavior, short-term memory, and locomotor activity (PND60-62) and ex vivo analysis of cell viability, membrane permeability, glutamate uptake, and susceptibility to in vitro glutamate challenge in hippocampal and cortical slices from PND65. A single isoflurane (3%, 2 h) exposure at PND7 did not acutely alter cell viability in cortical and hippocampal slices of infant rats (PND8) per se and did not alter slice susceptibility to in vitro glutamate challenge. In rat’s adulthood, behavioral analysis revealed that the neonatal isoflurane exposure did not alter anxiety-like behavior and locomotor activity (open field and rotarod tests). However, isoflurane exposure impaired short-term memory evaluated in the novel object recognition task. Ex vivo analysis of brain slices showed isoflurane neonatal exposure selectively decreased cell viability and glutamate uptake in cortical slices, but it did not alter hippocampal slice viability or glutamate uptake (PND65). Isoflurane exposure did not alter in vitro glutamate-induced neurotoxicity to slices, and isoflurane exposure caused no significant long-term damage to cell membranes in hippocampal or cortical slices. These findings indicate that a single neonatal isoflurane exposure did not promote acute damage; however, it reduced cortical, but not hippocampal, slice viability and glutamate uptake in the adulthood. Additionally, behavioral analysis showed neonatal isoflurane exposure induces short-term recognition memory impairment, consolidating that neonatal exposure to volatile anesthetics may lead to behavioral impairment in the adulthood, although it may damage brain regions differentially.
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The financial support agencies had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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Funding
This research was supported by grants from Brazilian funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) — Instituto Nacional de Ciência e Tecnologia (INCT for Excitotoxicity and Neuroprotection); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PVE 052/2012; CAPES-FCT 2014), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC)—Programa de Apoio aos Núcleos de Excelência (PRONEX — Project NENASC); and by Portuguese funding agencies: Fundação para a Ciência e Tecnologia (FCT, Portugal) — (Strategic Project 2015-UID/NEU/04539/2013); COMPETE-FEDER (POCI-01–0145-FEDER-007400); Centro 2020 Regional Operational Programmes (CENTRO-01–0145-FEDER-000012: HealthyAging2020 and CENTRO-01–0145-FEDER-000008: BrainHealth 2020). C.I.T. and R.D.P. are recipient of research fellowship from CNPq.
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Conceptualization and design of the study: C.I. Tasca, L.F. de Oliveira, R.D. Prediger and F.C. Pereira; material preparation and methodology: L.F. de Oliveira, G.G. Poluceno, T.B. Sampaio, L.C. Constantino, A.P. Costa, W.C. Martins, T. Dal-Cim, K.A. Oliveira, F.K. Ludka; formal analysis and investigation: L.F. de Oliveira, G.G. Poluceno, T.B. Sampaio, L.C. Constantino, A.P. Costa, W.C. Martins, T. Dal-Cim, K.A. Oliveira, F.K. Ludka; writing — original draft preparation: G.G. Poluceno and T.B. Sampaio; writing — review and editing: C.I. Tasca, L.C. Constantino, T. B. Sampaio and F.C. Pereira; funding acquisition: C.I. Tasca, R.D. Prediger and F.C. Pereira; Supervision: C.I. Tasca and F.C. Pereira.
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Experiments followed the “Principles of Laboratory Animal Care” (NIH 2011) and were approved by the Committee on the Ethics of Animal Experiments of the Federal University of Santa Catarina (CEUA/UFSC PP955).
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Ana Paula Costa´s current affiliation: Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
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de Oliveira, L.F., Poluceno, G.G., Sampaio, T.B. et al. Neonatal Isoflurane Exposure in Rats Impairs Short-Term Memory, Cell Viability, and Glutamate Uptake in Slices of the Frontal Cerebral Cortex, But Not the Hippocampus, in Adulthood. Neurotox Res 40, 1924–1936 (2022). https://doi.org/10.1007/s12640-022-00607-2
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DOI: https://doi.org/10.1007/s12640-022-00607-2