Sevoflurane and lipopolysaccharide-induced inflammation differentially affect γ-aminobutyric acid type A receptor-mediated tonic inhibition in the hippocampus of male mice

Khodaei, Shahin; Wang, Dian-Shi; Lee, Yulim; Chung, Woosuk; Orser, Beverley A.

doi:10.1016/j.bja.2022.09.013

Cited by 8 publications

(12 citation statements)

References 15 publications

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“…Second, the electrophysiology of synapses such as long-term potentiation/depression, EEG changes, or burst suppression was not measured. Previous studies have demonstrated that sevoflurane impaired synapse development and electrophysiological activity [ 23 , 61 – 64 ]. Last, we used intraperitoneal injection of ANX005 and NADNA to inhibit the expression of C1q and sialidase respectively, and we did not perform interventions at the gene and transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

Wang,

Liu,

Meng

et al. 2024

Cell Biosci

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Background Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms. Methods Neonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells. Results Repeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005. Conclusions Our findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

Wang,

Liu,

Meng

et al. 2024

Cell Biosci

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“…Mice were treated as per our previous studies. 7 , 9 Briefly, inflammation was induced by intraperitoneal injection of LPS that was derived from Escherichia coli (1 mg kg −1 ; O111:B4; Sigma-Aldrich, Oakville, ON, Canada). At this moderate dose, LPS induces neuroinflammation that persists for at least 24 h, as indicated by elevated levels of pro-inflammatory cytokines.…”

Section: Methodsmentioning

confidence: 99%

“…We observed previously that treatment with LPS and sevoflurane caused a sustained increase in a tonic inhibitory conductance in pyramidal neurones of the cornu ammonis 1 (CA1) region of the hippocampus. 9 This increase in tonic inhibition is likely because of increased cell-surface expression of extrasynaptic GABA Type A (GABA A ) receptors. 10 , 11 Importantly, increased tonic inhibition may have functional consequences, including reduced neuronal excitability, altered synaptic plasticity, and impaired cognition.…”

mentioning

confidence: 99%

Reduced excitatory neurotransmission in the hippocampus after inflammation and sevoflurane anaesthesia

Khodaei¹,

Wang²,

Orser³

2023

BJA Open

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“…Sevoflurane is an inhalational anaesthetic commonly used in surgery 14 . Studies have shown that sevoflurane affects cancer progression and inflammation by mediating gene expression and signaling pathways 15 , 16 . Another investigator has identified that inhibiting the NLRP3 inflammasome in the hippocampus alleviates sevoflurane-induced POCD in aged mice 17 .…”

Section: Introductionmentioning

confidence: 99%

mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice

Yang,

Zhong,

Sha

et al. 2024

Int. J. Biol. Sci.

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The activation of NLRP3 inflammasome in microglia is critical for neuroinflammation during postoperative cognitive dysfunction (POCD) induced by sevoflurane. However, the molecular mechanism by which sevoflurane activates the NLRP3 inflammasome in microglia remains unclear. The cGAS-STING pathway is an evolutionarily conserved inflammatory defense mechanism. The role of the cGAS-STING pathway in sevoflurane-induced NLRP3 inflammasome-dependent neuroinflammation and the underlying mechanisms require further investigation. We found that prolonged anesthesia with sevoflurane induced cognitive dysfunction and triggered the neuroinflammation characterized by the activation of NLRP3 inflammasome in vivo . Interestingly, the cGAS-STING pathway was activated in the hippocampus of mice receiving sevoflurane. While the blockade of cGAS with RU.521 attenuated cognitive dysfunction and NLRP3 inflammasome activation in mice. In vitro , we found that sevoflurane treatment significantly activated the cGAS-STING pathway in microglia, while RU.521 pre-treatment robustly inhibited sevoflurane-induced NLRP3 inflammasome activation. Mechanistically, sevoflurane-induced mitochondrial fission in microglia and released mitochondrial DNA (mtDNA) into the cytoplasm, which could be abolished with Mdivi-1. Blocking the mtDNA release via the mPTP-VDAC channel inhibitor attenuated sevoflurane-induced mtDNA cytosolic escape and reduced cGAS-STING pathway activation in microglia, finally inhibiting the NLRP3 inflammasome activation. Therefore, regulating neuroinflammation by targeting the cGAS-STING pathway may provide a novel therapeutic target for POCD.

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Sevoflurane and lipopolysaccharide-induced inflammation differentially affect γ-aminobutyric acid type A receptor-mediated tonic inhibition in the hippocampus of male mice

Cited by 8 publications

References 15 publications

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

Reduced excitatory neurotransmission in the hippocampus after inflammation and sevoflurane anaesthesia

mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice

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