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Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity AIDN: A Translational Neuroscience Approach
Published on: June 11, 2017
Neonatal sevoflurane exposure disrupts the lung-brain axis and drives microglial neuroinflammation and cognitive
Lirong Liang1, Shuhui Cao2, Youyi Zhao1
1Department of Anesthesiology, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.
Background:
Neonatal sevoflurane exposure in mice induces microglial activation and long-term cognitive deficits, a finding that raises significant concerns for pediatric anesthesia. The lung-brain axis, a critical pathway mediating pulmonary-central nervous system communication, is indispensable for maintaining organismal homeostasis. However, existing research on anesthetic neurotoxicity has focused predominantly on central mechanisms, with insufficient attention to the lung-a major immune organ with extensive bidirectional crosstalk with the brain. Herein, we aim to explore the lung-brain interactions underlying long-term cognitive sequelae of neonatal sevoflurane exposure.
Methods:
C57BL/6J mice were selected and exposed to 3% sevoflurane for 2 h daily on postnatal days 6-8. Upon reaching adulthood, cognitive function and microglial activation status were evaluated. At 4 weeks post-exposure, 16S rRNA gene sequencing and metabolomic analysis were performed respectively to characterize the structure of the pulmonary microbiota and the metabolite profile. Proximity ligation assay (PLA), fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET), and co-immunoprecipitation (COIP) were employed to investigate the molecular mechanisms by which lung-derived metabolites mediate brain effects. Additionally, rescue experiments were conducted by administering the sphingosine-1-phosphate receptor modulator FTY720 and Moce to validate the aforementioned effects.
Results:
Repeated neonatal sevoflurane exposure impaired adult cognitive function, induced microglial activation, and was concurrent with pulmonary microbiome dysbiosis and metabolic alterations. Notably, sphingosine-a key membrane lipid-was significantly decreased. Intratracheal administration of FTY720, a sphingosine analog, alleviated neuroinflammation and ameliorated cognitive deficits. Mechanistically, sevoflurane exposure upregulated HDAC1 and downregulated KLF4, whereas FTY720 significantly rescued these sevoflurane-induced expression aberrations, implicating the HDAC1/KLF4 axis in the regulation of neuroinflammation. Additionally, MOCE significantly alleviated neuroinflammation and ameliorated cognitive deficits.
Conclusions:
Developmental sevoflurane exposure induces microglial activation and cognitive decline via a pulmonary dysbiosis-sphingosine reduction cascade. The sphingosine-1-phosphate receptor modulator FTY720 mitigates this impairment by regulating microglial activation and neuroinflammation. These findings reveal novel mechanisms of anesthetic neurotoxicity and identify potential neuroprotective targets for pediatric anesthesia.
Insights
Neonatal sevoflurane exposure causes cognitive deficits by disrupting the lung microbiome and reducing sphingosine. FTY720, a sphingosine analog, reverses these effects, offering neuroprotection in pediatric anesthesia.
Area of Science:
- Neuroscience
- Anesthesiology
- Immunology
Background:
- Neonatal sevoflurane exposure is linked to cognitive deficits and microglial activation.
- The lung-brain axis is crucial for homeostasis, but its role in anesthetic neurotoxicity is understudied.
- Anesthetic neurotoxicity research has primarily focused on central mechanisms, neglecting the lung's immune role.
Purpose of the Study:
- To investigate lung-brain interactions in neonatal sevoflurane-induced cognitive deficits.
- To explore the mechanisms underlying long-term cognitive sequelae of sevoflurane exposure.
- To identify potential therapeutic targets for mitigating anesthetic neurotoxicity.
Main Methods:
- Mice exposed to sevoflurane on postnatal days 6-8 were assessed for cognitive function and microglial activation.
- Pulmonary microbiota and metabolite profiles were analyzed using 16S rRNA sequencing and metabolomics.
- Molecular mechanisms were investigated using PLA, FLIM-FRET, and COIP, with rescue experiments using FTY720 and MOCE.
Main Results:
- Sevoflurane exposure impaired cognitive function, increased microglial activation, and caused pulmonary dysbiosis and metabolic changes, notably decreased sphingosine.
- Intratracheal FTY720 administration ameliorated neuroinflammation and cognitive deficits.
- FTY720 rescued sevoflurane-induced aberrations in the HDAC1/KLF4 axis, suggesting its role in neuroinflammation regulation.
Conclusions:
- Developmental sevoflurane exposure triggers microglial activation and cognitive decline through a pulmonary dysbiosis-sphingosine reduction pathway.
- The sphingosine-1-phosphate receptor modulator FTY720 mitigates sevoflurane-induced impairment by modulating microglial activation and neuroinflammation.
- These findings highlight novel mechanisms of anesthetic neurotoxicity and suggest FTY720 as a potential neuroprotective agent in pediatric anesthesia.
