Exposure to general anesthesia (GA) during the postnatal period is associated with neuroinflammation and long-term neurocognitive impairment in preclinical and clinical settings. Pyroptosis is a novel type of programmed cell death that, along with inflammation, has been found to play an important role in the mechanism of diverse neurological diseases. However, its roles in GA-induced neuroinflammation and neurocognitive impairment in the developing brain have not been investigated. Rats at postnatal day 6 or primary hippocampal neurons at 9 days in vitro received 3% sevoflurane for 2 h daily for three consecutive days. A pharmacological inhibitor of nuclear factor (NF)-κB (BAY 11-7082) was administered to suppress NF-κB activation. Histological and biochemical analyses were performed to assess the pyroptosis as well as neuronal and synaptic damage both in vivo and in vitro. In addition, behavioral tests were performed to evaluate neurocognitive ability in rats. Repeated sevoflurane exposure activated NF-κB-mediated pyroptosis and neuroinflammation in the hippocampus in developing rats, damaged the neuronal morphology and synaptic integrity, and induced neurocognitive impairment in rats. BAY 11-7082 treatment suppressed the activation of pyroptosis, attenuated the neuronal and synaptic damage, and ameliorated the neurocognitive impairment induced by repeated sevoflurane administration to developing rats. Repeated sevoflurane GA may induce neuroinflammation and neurocognitive impairment in developing rats via the activation of NF-κB-mediated pyroptosis. Our findings characterize a novel role of pyroptosis as a potential therapeutic target in neuroinflammation after repeated neonatal GA.

中文翻译：

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反复新生儿七氟醚通过 NF-κB 介导的细胞焦亡引起神经认知障碍

产后暴露于全身麻醉 (GA) 与临床前和临床环境中的神经炎症和长期神经认知障碍有关。焦亡是一种新型的程序性细胞死亡，与炎症一起，已被发现在多种神经系统疾病的机制中发挥重要作用。然而，尚未研究其在发育中的大脑中 GA 诱导的神经炎症和神经认知障碍中的作用。出生后第 6 天的大鼠或体外第 9 天的原代海马神经元接受 3% 的七氟醚，每天 2 小时，连续三天。给予核因子 (NF)-κB (BAY 11-7082) 的药理学抑制剂以抑制 NF-κB 活化。进行组织学和生化分析以评估体内和体外的细胞焦亡以及神经元和突触损伤。此外，还进行了行为测试以评估大鼠的神经认知能力。反复接触七氟醚会激活发育中大鼠海马中 NF-κB 介导的细胞焦亡和神经炎症，损害神经元形态和突触完整性，并诱导大鼠神经认知障碍。BAY 11-7082 治疗抑制了细胞焦亡的激活，减轻了神经元和突触的损伤，并改善了反复给予发育中的大鼠七氟醚引起的神经认知障碍。重复七氟醚 GA 可能通过激活 NF-κB 介导的细胞焦亡诱导发育中大鼠的神经炎症和神经认知障碍。