Sevoflurane induces inflammation of microglia in hippocampus of neonatal rats by inhibiting Wnt/β-Catenin/CaMKIV pathway

Wang, Fengjuan; Li, Chuangang; Shao, Jianhui; Ma, Jinfeng

doi:10.1016/j.jphs.2021.02.004

Cited by 26 publications

(20 citation statements)

References 35 publications

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“…Fourteen months old aged mice were treated with 3% sevoflurane for 6 h to establish the POD mouse model. We confirmed the similar phenomenon of previous study showing that sevoflurane induces microglial activation ( Wang et al, 2021 ). We performed the immunofluorescence staining of Iba1 ( Figure 1A ), a recognized maker for microglia, to detect the microglia activation and found there’s significant increased Iba1 + cell numbers ( Figure 1B ) and microglial intensity ( Figure 1C ) in sevoflurane mice hippocampus.…”

Section: Resultssupporting

confidence: 93%

“…Although the activation of microglial inflammatory responses and apoptosis induced by anesthetics are thought to play a vital role in the occurrence of cognitive disorders, the mechanisms of these phenomena remain unclear. As indicated earlier, sevoflurane can induce microglial activation followed by inflammatory responses, and excessive microglial activation further leads to the loss of neurons; these are believed to be crucial factors in POD (Dai et al, 2015;Wang et al, 2021). Here, by targeting microglia, we confirmed that it could be activated by clinical concentrations of sevoflurane in the mouse brain.…”

Section: Discussionsupporting

confidence: 83%

“…Previous studies have illustrated the neurotoxicity of general anesthetics on microglia and neurons. For instance, sevoflurane triggers the inflammatory response of microglia in the hippocampus by blocking the Wnt/β-Catenin/CaMKIV pathway ( Wang et al, 2021 ). Sevoflurane also induced neuronal apoptosis through the PI3K/AKT/FOXO3a pathway ( Dong et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

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ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation

Gao

Sun

et al. 2021

Front. Cell. Neurosci.

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Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation

Gao

Sun

et al. 2021

Front. Cell. Neurosci.

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“…Abnormalities in many of these processes, however, have the potential to result in lasting health-related consequences. 39 Such a possibility is supported by our findings of epigenomic changes in multiple genes induced by neonatal exposure to SEVO. Such epigenomic changes may not only underlie deficiencies in the development and functioning of the central nervous system, but they may also be linked to regulation of stress responses, metabolic processes, vasculature development, and blood circulation, among others.…”

Section: Discussionsupporting

confidence: 61%

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats

Yang

Tong

Brant³

et al. 2022

Anesthesia &Amp; Analgesia

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BACKGROUND: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic’s long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

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“…The hippocampus, a center for learning and memory, robustly expresses IL-1β receptor, which play key roles in learning and memory as pro-inflammatory factor receptors. However, in the pathological state, such as exposure to sevoflurane, the hippocampus is more vulnerable to the damage induced by pro-inflammatory factors, thus leading to cognitive impairment [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

IL-17A deletion reduces sevoflurane-induced neurocognitive impairment in neonatal mice by inhibiting NF-κB signaling pathway

Zhang

Yin

et al. 2022

Bioengineered

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We investigated the role of IL-17A in sevoflurane-inducedneurocognitive impairment in neonatal mice. Seventy-two wild-type (WT) and 42 IL-17A knockout (KO) neonatal mice were randomly divided into WT ( n = 36), IL-17A −/− ( n = 6), sevoflurane (Sev, n = 36), and IL-17A −/− + sevoflurane (IL-17A −/− + Sev, n = 36) groups. The latter two groups were given 3% sevoflurane for 2 h per day on postnatal days (P) 6–8. Behavioral experiments were performed on P30–36. At P37, RNA sequencing and qRT-PCR of the hippocampus was performed, neurons were detected by Nissl staining, and neuropathological changes were evaluated by HE staining. NF-κB pathway-related proteins were evaluated by western blot and immunofluorescence analyses, IL-1β and IL-6 levels were assessed by ELISA. RNA sequencing identified 131 differentially expressed genes, highlighting several enriched biological processes (chemokine activity, immune response, extracellular region, extracellular space, inflammatory response) and signaling pathways (IL-17 signaling pathway, chemokine signaling pathway, cytokine–cytokine receptor interaction, ECM–receptor interaction and influenza A). Repeated sevoflurane exposures induced long-term cognitive impairment in WT mice. The cognitive impairment was comparatively less severe in IL-17A KO mice. In addition, the increased levels of NF-κB p65, iNOS, COX-2, IL-17A, IL-6 and IL-1β, reduced neuronal numbers and neuropathological changes were ameliorated in neonatal mice in the IL-17A −/− + Sev group compared with neonatal mice in Sev group. IL-17A deletion protects against long-term cognitive impairment induced by repeated sevoflurane exposure in neonatal mice. The underlying mechanism may relate to inhibiting NF-κB signaling pathway as well as the reducing neuroinflammation.

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Sevoflurane induces inflammation of microglia in hippocampus of neonatal rats by inhibiting Wnt/β-Catenin/CaMKIV pathway

Cited by 26 publications

References 35 publications

ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation

ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats

IL-17A deletion reduces sevoflurane-induced neurocognitive impairment in neonatal mice by inhibiting NF-κB signaling pathway

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