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

Abstract

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.

The roles of ubiquitination and deubiquitination of NLRP3 inflammasome in inflammation-related diseases: A review

“…This led to a downregulation of hippocampal NLRP3, IκBα, p65, and MDA expression, and an upregulation of SOD and CAT protein levels. As a result, hippocampal inflammation and OS were inhibited, which in turn alleviated cognitive impairment and neurotoxicity in the rats [ 90 ]. In a mouse model of oxygen–glucose deprivation/reperfusion (OGD/R)-induced myocardial I/R, pubescenoside A (PBA) demonstrated selective and covalent binding to the conserved cysteine (Cys) residues Cys77 and Cys434 of Keap1.…”

The role of sevoflurane in postoperative cognitive dysfunction

“…In a neonatal rat experiment, Zhu et al 17 found that USP1-associated factor 1 inhibits the degradation of NOD-like receptor protein 3 through the ubiquitin-proteasome pathway, which can aggravate sevoflurane-induced POCD. Therefore, downregulation of USP1-associated factor 1 reduces cognitive impairment.…”