Prenatal Sevoflurane Exposure Impairs the Learning and Memory of Rat Offspring via HMGB1-Induced NLRP3/ASC Inflammasome Activation

Abstract

The neurotoxic effects of sevoflurane anesthesia on the immature nervous system have aroused public concern, but the specific effects and mechanism remain poorly understood. Pyroptosis caused by the activation of the NLRP3 inflammasome is pivotal for cell survival and acts as a key player in cognitive impairment. This study was carried out to determine the critical role of the NLRP3 inflammasome and high-mobility group box 1 (HMGB1) in sevoflurane-induced cognitive impairment. On gestational day 20 (G20), 3% sevoflurane was administered for 4 h to pregnant rats. The hippocampus and cerebral cortex of the offspring were harvested at postnatal day 1 (P1) for Western blotting and immunofluorescence staining. Pregnant rat sevoflurane exposure increased the protein levels of NLRP3, ASC, cleaved-caspase 1 (p20), mature-IL-1β (m-IL-1β), and HMGB1 in the cerebral cortex and hippocampus of offspring rats. More microglial cells of offspring were also observed after sevoflurane anesthesia. The Morris water maze (MWM) test was implemented to evaluate cognitive function from postnatal day 30 (P30) to postnatal 35 (P35) of offspring. The sevoflurane-treated offspring took longer than the control rats to find the MWM platform during the learning phase. Furthermore, they had a longer travel distance and less time in the target quadrant than the control rats in the probe trial. Maternal intraperitoneal injection of glycyrrhizin (an inhibitor of HMGB1) attenuated the sevoflurane-induced microglia and NLRP3/ASC inflammasome activation and cognitive impairment of offspring. Simultaneously, the sevoflurane-induced increase in Toll-like receptors (TLR4) and nuclear factor-κB (NF-κB) was significantly reduced by glycyrrhizin. We concluded that the HMGB1 inhibitor may repress the sevoflurane-induced activation of the NLRP3/ASC inflammasome and cognitive dysfunction and that TLR4/NF-κB signaling maybe the key pathway, at least in part.

Advances in the roles of glycyrrhizic acid in cancer therapy

“…Paclitaxel induces disruption of axonal transport through microtubule stabilization, changes in mitochondrial morphology and function, and inflammatory responses, leading to axonal symmetry damage and loss of nerve fibers, and subsequent neurotoxicity ( Niznansky et al, 2022 ). Increasing studies have suggested that GL could provide neuroprotection in nerve system due to its strong anti-inflammatory, anti-apoptosis, antioxidant and autophagy regulation properties ( Kim et al, 2012 ; Yang et al, 2018 ; Gendy et al, 2023 ; Shan et al, 2023 ). A recent study has shown that GL alleviated paclitaxel-induced neurotoxicity in vitro and in vivo by inhibiting the neuronal uptake mediated by organic anion transport peptides (OATPs), which are the main neuronal transporters of paclitaxel ( Klein et al, 2023 ).…”

The role of pyroptosis in cognitive impairment

“…It was reported that NLRP3 inflammasome-mediated pyroptosis directly led to cognitive impairment in PND mice model induced by . NF-κB and HMGB1 induced pyroptosis were also elucidated in PND, NF-κB inhibitor or HMGB1 inhibitor treatment effectively improved PND by significantly inhibiting pyroptosis (Dai et al, 2021;Shan et al, 2023). found that esketamine improved POCD in aged rats and alleviated the pyroptosis of astrocytes after LPS exposure, moreover, an underlying connection between STING/TBK1 signaling pathway and caspase-1-mediated pyroptosis was indicated, which required further research.…”

“…The mitochondrial protectant dexpramipexole (DPX) could sustain mitochondrial function and inhibit NLRP3/caspase-1 pyroptosis pathway, thus ameliorating neuroinflammation and cognitive impairment in SAE (Zhang et al, 2023). Sevoflurane was reported to activate HMGB1-induced NLRP3/ASC inflammasome, induce pyroptosis, and impair cognitive function in PND (Shan et al, 2023), however, in SAE, sevoflurane could act as protective role. Chen et al (2022) demonstrated that sevoflurane could improve cognitive dysfunction by inhibiting the NLRP3-dependent caspase-1/11-GSDMD pathway, in which SIRT1 played a key role.…”