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Repeated 2% sevoflurane administration in 7‑ and 60-day-old rats

Neurotoxicity and neurocognitive dysfunction

Wiederholte Anwendung von Sevofluran 2 % bei 7 und 60 Tage alten Ratten

Neurotoxizität und neurokognitive Dysfunktion

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Abstract

Background

Sevoflurane is one of the most widely used inhalation anesthetics in pediatric anesthesia. A large number of studies have demonstrated that repeated treatment with high concentrations or long durations of sevoflurane anesthesia during the neonatal period can induce neuroapoptosis and long-term learning disability. In clinical practice, we observed that a subset of patients underwent minor surgery under sevoflurane anesthesia more than once from birth to adolescence. Therefore, this research was conducted to investigate whether a 2% concentration of sevoflurane (clinically relevant usage of sevoflurane) for 1 h (a short duration) can induce neuroapoptosis and neurocognitive dysfunction in adolescent rats that received sevoflurane (2% for 1 h) during the neonatal period.

Material and methods

Group I: neonatal rats at postnatal day 7 (PND-7) were treated with oxygen under controlled conditions and then raised to PND-60. Group II: PND-7 rats were treated with 2% sevoflurane for 1 h and then raised to PND-60. Group III: the PND-60 rats were treated with 2% sevoflurane for 1 h and in group IV the PND-7 rats were treated with 2% sevoflurane for 1 h and then anesthetized with 2% sevoflurane for 1 h at PND-60 again. The expression of caspase-3, Bax and Bcl-2 in the hippocampal dentate gyrus (DG) were measured by Western blot analysis. Neuroapoptosis in the hippocampal DG was assessed using NeuN/caspase-3 double-immunofluorescence staining. Spatial reference memory was tested by the Morris water maze test.

Results

The present data showed that sevoflurane (2% for 1 h) did not induce obvious hippocampal neuroapoptosis in the PND-7 rats and PND-60 rats; their performance in hippocampal-dependent spatial memory was not significantly impaired; however, the rats in group IV showed poor performance in the Morris water maze test and the neuroapoptosis in group IV was significantly increased.

Conclusion

Our findings suggested that sevoflurane can induce neuroapoptosis and cognitive dysfunction in adolescent rats that received repeated sevoflurane (2% for 1 h) during the postnatal period. These findings will promote further studies to investigate the effects of repeated sevoflurane exposure on the development of the central nervous system and function of learning and memory, as well as the underlying mechanisms in vitro and in vivo.

Zusammenfassung

Hintergrund

Sevofluran ist eines der am häufigsten verwendeten Inhalationsanästhetika in der pädiatrischen Anästhesie. Zahlreiche Studien haben gezeigt, dass eine wiederholte Behandlung mit hohen Konzentrationen oder die Langzeitanwendung des Anästhetikums Sevofluran während in der neonatalen Phase Neuroapoptose und langfristige Lernbehinderungen verursachen kann. In der klinischen Praxis beobachteten wir, dass ein Teil der Patienten bei kleineren Operationen von der Geburt bis zur Adoleszenz mehrfach mit Sevofluran behandelt wurde. Diese Studie wurde daher durchgeführt, um zu untersuchen, ob eine 2 %ige Konzentration von Sevofluran (klinisch relevante Anwendung von Sevofluran) für 1 h (einen kurzen Zeitraum) Neuroapoptose und neurokognitive Dysfunktion bei adoleszenten Ratten induzieren kann, die Sevofluran (2 % für 1 h) während der neonatalen Phase erhielten.

Material und Methoden

Gruppe I: Neonatale Ratten wurden am 7. postnatalen Tag (PND-7) unter kontrollierten Bedingungen mit Sauerstoff behandelt und dann bis PND-60 aufgezogen. Gruppe II: PND-7-Ratten wurden mit Sevofluran 2 % für 1 h behandelt und dann bis PND-60 aufgezogen. Gruppe III: Die PND-60-Ratten wurden für 1 h mit Sevofluran 2 % behandelt, und in Gruppe IV wurden die PND-7-Ratten für 1 h mit Sevofluran 2 % behandelt und dann nochmals am PND-60 für 1 h mit Sevofluran 2 % anästhesiert. Die Expression von Caspase-3, Bax und Bcl-2 im Gyrus dentatus (GD) des Hippokampus wurde mittels Western-Blot-Analyse bestimmt. Die Neuroapoptose im GD des Hippokampus wurde mittels NeuN/Caspase-3-Doppelimmunofluoreszenzfärbung beurteilt.

Ergebnisse

Die vorliegenden Daten zeigten, dass Sevofluran (2 % für 1 h) keine ersichtliche Neuroapoptose im Hippokampus bei den PND-7-Ratten und den PND-60-Ratten induzierte; ihre Leistung im Hippokampus-abhängigen Raumgedächtnis war nicht signifikant eingeschränkt. Jedoch zeigten die Ratten in Gruppe IV eine schwache Leistung im Morris-Wasserlabyrinth-Test, und die Neuroapoptose in Gruppe IV war signifikant erhöht.

Schlussfolgerung

Unsere Ergebnisse zeigten, dass Sevofluran Neuroapoptose und kognitive Dysfunktion bei adoleszenten Ratten induzieren kann, die während der postnatalen Phase wiederholt mit Sevofluran (2 % for 1 h) behandelt wurden. Diese Ergebnisse werden weitere Studien vorantreiben, um die Effekte einer wiederholten Sevofluranexposition auf die Entwicklung des Zentralnervensystems und die Lern- und Gedächtnisfunktion sowie die zugrunde liegenden Mechanismen in vitro und in vivo zu untersuchen.

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Funding

This work was supported by the National Natural Science Foundation of China (81171013), Key Subject of Colleges and Universities Natural Science Foundation of Jiangsu Province (10KJA320052).

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Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Guangzhou Road 300, 210029, Nanjing, China

    He Huang, Cun-Ming Liu, Jie Sun, Wen-Jie Jin & Jing Chen

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China

    Yu-Qing Wu

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  1. He Huang
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Correspondence to Jing Chen.

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Conflict of interest

H. Huang, C.‑M. Liu, J. Sun, W.‑J. Jin, Y.‑Q. Wu and J. Chen declare that they have no competing interests.

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Huang, H., Liu, CM., Sun, J. et al. Repeated 2% sevoflurane administration in 7‑ and 60-day-old rats. Anaesthesist 66, 850–857 (2017). https://doi.org/10.1007/s00101-017-0359-4

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