Department of Anesthesiology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, China.
Department of Anesthesiology, The Affiliated Shanghai East Hospital of Tongji University, China.
J Toxicol Sci. 2022;47(9):349-357. doi: 10.2131/jts.47.349.
Evidence has shown that suppression of the activation of NLRP3 inflammasome could ameliorate surgery/sevoflurane (SEV)-induced post-operative cognitive dysfunction (POCD). However, the underlying mechanisms remain unclear. UAF1 acts as a binding partner of USP1, which inhibits the ubiquitination-mediated degradation of NLRP3, indicating that UAF1 may be implicated in POCD through regulating the NLRP3 inflammasome. Here, we studied the role of UAF1/NLRP3 in SEV-induced cognitive impairment and neurotoxicity in rats. Neonatal rats were randomly divided into control, SEV, SEV+AAV-shNC and SEV+AAV-shUAF1 (UAF1-downregulated) groups. Morris water maze (MWM) test was applied to assess cognitive impairment. TUNEL staining, qRT-PCR and ELISA were used to assess the apoptosis and inflammation markers, respectively. The levels of superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) were quantified to determine oxidative stress. The results showed that SEV treatment led to significant cognitive impairment, increased apoptosis in hippocampal tissues, upregulation of MDA and inflammatory factors (TNF-α, IL-1β, IL-18), as well as a decrease in SOD and CAT levels. All of the above observations were reversed by UAF1 downregulation. Furthermore, depletion of UAF1 neutralized SEV-mediated increase in p-NLRP3, p-IκBα and p-p65 levels. Altogether, the current study demonstrated that knockdown of UAF1 could alleviate SEV-induced cognitive impairment and neurotoxicity in rats by inhibiting pro-inflammatory signaling and oxidative stress.
证据表明，抑制 NLRP3 炎性小体的激活可以改善手术/七氟醚（SEV）诱导的术后认知功能障碍（POCD）。然而，其潜在机制尚不清楚。UAF1 作为 USP1 的结合伴侣，可抑制 NLRP3 的泛素化介导降解，表明 UAF1 可能通过调节 NLRP3 炎性小体参与 POCD。在这里，我们研究了 UAF1/NLRP3 在 SEV 诱导的大鼠认知障碍和神经毒性中的作用。新生大鼠随机分为对照组、SEV 组、SEV+AAV-shNC 组和 SEV+AAV-shUAF1（UAF1 下调）组。采用 Morris 水迷宫（MWM）测试评估认知障碍。TUNEL 染色、qRT-PCR 和 ELISA 分别用于评估细胞凋亡和炎症标志物。定量测定超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和丙二醛（MDA）水平，以确定氧化应激。结果表明，SEV 处理导致明显的认知障碍，海马组织细胞凋亡增加，MDA 和炎症因子（TNF-α、IL-1β、IL-18）水平上调，SOD 和 CAT 水平降低。UAF1 下调逆转了所有上述观察结果。此外，UAF1 的耗竭中和了 SEV 介导的 p-NLRP3、p-IκBα 和 p-p65 水平的增加。总之，本研究表明，下调 UAF1 可通过抑制促炎信号和氧化应激缓解 SEV 诱导的大鼠认知障碍和神经毒性。
