• Nemanja Useinovic, Stefan Maksimovic, Cole Liechty, Omar H Cabrera, Nidia Quillinan, and Vesna Jevtovic-Todorovic.
• Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address: nemanja.useinovic@cuanschutz.edu.
• Br J Anaesth. 2022 Oct 1; 129 (4): 555566555-566.

BackgroundGeneral anaesthesia in the neonatal period has detrimental effects on the developing mammalian brain. The impact of underlying inflammation on anaesthesia-induced developmental neurotoxicity remains largely unknown.MethodsPostnatal day 7 (PND7) rats were randomly assigned to receive sevoflurane (3 vol% for 3 h) or carrier gas 12 h after bacterial lipopolysaccharide (LPS; 1 μg g-1) or vehicle injection. Pharmacological inhibition of caspase-1 by Vx-765 (two doses of 50 μg g-1 body weight) was used to investigate mechanistic pathways of neuronal injury. Histomorphological injury and molecular changes were quantified 2 h after the end of anaesthesia. Long-term functional deficits were tested at 5-8 weeks of age using a battery of behavioural tests in the memory and anxiety domains.ResultsSevoflurane or LPS treatment increased activated caspase-3 and caspase-9 expression in the hippocampal subiculum and CA1, which was greater when sevoflurane was administered in the setting of LPS-induced inflammation. Neuronal injury induced by LPS+sevoflurane treatment resulted in sex-specific behavioural outcomes when rats were tested at 5-8 weeks of age, including learning and memory deficits in males and heightened anxiety-related behaviour in females. Hippocampal caspase-1 and NLRP1 (NLR family pyrin domain containing 1), but not NLRP3, were upregulated by LPS or LPS+sevoflurane treatment, along with related proinflammatory cytokines, interleukin (IL)-1β, and IL-18. Pretreatment with Vx-765, a selective caspase-1 inhibitor, led to reduced IL-1β in LPS and LPS+sevoflurane groups. Caspase-1 inhibition by Vx-765 significantly decreased activated caspase-3 and caspase-9 immunoreactivity in the subiculum.ConclusionsSystemic inflammation promotes developmental neurotoxicity by worsening anaesthesia-induced neuronal damage with sex-specific behavioural outcomes. This highlights the importance of studying anaesthesia-induced neurotoxicity in more clinically relevant settings.Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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