Knockdown of UAF1 alleviates sevoflurane-induced cognitive impairment and neurotoxicity in rats by inhibiting pro-inflammatory signaling and oxidative stress.

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-1ß, 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.