Febuxostat Prevents the Cytotoxicity of Propofol in Brain Endothelial Cells

Abstract

Background and purpose: A high risk of brain injury has been reported with the usage of general anesthetics such as propofol in infants. Experimental data indicated that oxidative stress and inflammation are involved in the neurotoxicity induced by propofol. Febuxostat is a novel anti-gout agent recently reported to exert an anti-inflammatory effect. The present study aims to investigate the protective property of febuxostat against the cytotoxicity of propofol in brain endothelial cells as well as the underlying preliminary mechanism. Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to screen the optimized incubation concentration of febuxostat. bEnd.3 brain endothelial cells were stimulated with 2% propofol in the presence or absence of febuxostat (10, 20 μM) for 24 h. The lactate dehydrogenase (LDH) release assay was conducted to detect cytotoxicity. The reactive oxygen species (ROS) levels were evaluated using dichloro-dihydro-fluorescein diacetate (DCFH-DA) staining, and the concentration of reduced glutathione (GSH) was determined using a commercial kit. The expressions of TNF-α, IL-6, IL-12, CXCL-1, PDPN, CXCL8, VCAM-1, and E-selectin were determined using a quantitative real-time polymerase chain reaction (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). Western blot and qRT-PCR were utilized to determine the expressions of COX-2 and KLF6. The production of PGE 2 was evaluated by ELISA. Results: First, increased LDH release induced by propofol was significantly suppressed by febuxostat. The oxidative stress (elevated ROS levels and decreased GSH level) induced by propofol was alleviated by febuxostat. Second, the upregulated inflammatory factors (TNF-α, IL-6, and IL-12), pro-inflammatory chemokines (CXCL-1, PDPN, and CXCL8), adhesion molecules (VCAM-1 and E-selectin), and inflammatory mediators (COX-2 and PGE 2 ) induced by propofol were greatly downregulated by febuxostat. Lastly, the expression of KLF6 was significantly suppressed by propofol but greatly elevated by febuxostat. Conclusion: Febuxostat prevented the cytotoxicity of propofol in brain endothelial cells by alleviating oxidative stress and inflammatory response through KLF6.

Febuxostat Alleviates Allergic Rhinitis by Inhibiting Inflammation and Monocyte Adhesion in Human Nasal Epithelial Cells via Regulating KLF6

“…KLF6 is involved in multiple types of cellular progression, such as cell development, growth, signaling transition, proliferation, differentiation, and apoptosis, and the deficiency of KLF is closely associated with the development of malignant tumors [ 38 , 39 ]. Recently, KLF6 was reported to regulate the expression of CAMs and mediate adhesion between endothelial cells and monocytes [ 21 , 40 ]. In this study, we found that KLF6 was dramatically downregulated in histamine-treated hNECs but elevated by febuxostat, which is consistent with previous reports [ 21 ].…”

“…Recently, KLF6 was reported to regulate the expression of CAMs and mediate adhesion between endothelial cells and monocytes [ 21 , 40 ]. In this study, we found that KLF6 was dramatically downregulated in histamine-treated hNECs but elevated by febuxostat, which is consistent with previous reports [ 21 ]. Further, we found that the inhibitory effects of febuxostat on the expression of CAMs and adhesion between histamine-treated hNECs and monocytes were significantly abolished by the knockdown of KLF6, which indicated that febuxostat exerted an anti-inflammatory effect by activating KLF6.…”

“…Animal experiments revealed that febuxostat showed a promising protective property in renal ischemia-reperfusion injury [ 18 ], diabetic nephropathy (DN) [ 19 ], and myocardial ischemia-reperfusion injury [ 20 ] by inhibiting oxidative stress. Recently, febuxostat was reported to suppress adhesion between monocytes and endothelial cells by regulating the expression level of CAMs, which is associated with the activation of KLF6 [ 21 ]. In this study, we explored the inhibitory function of febuxostat on inflammation to determine the therapeutic function of febuxostat on AR.…”

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy

“…Herein, KLF6 knockout signi cantly increased, while its overexpression markedly reduced ROS levels in AML12 cells after hypoxia / reoxygenation. Recent studies have also shown that febuxostat inhibits oxidative stress and in ammatory responses by up-regulating KLF6, thereby reducing the toxicity of propofol to brain endothelial cells [32]. Sitagliptin attenuates high glucose-induced oxidative stress and in ammation and increases the permeability of renal tubular endothelial cells by elevating KLF6 expression [33].…”

High-Throughput mRNA Sequencing Reveals Potential Therapeutic Targets of Febuxostat in Secondary Injury After Intracerebral Hemorrhage

“…Febuxostat is an orally administered, nonpurine-selective xanthine oxidase inhibitor approved by the Food and Drug Administration (FDA) in 2009 for the management of hyperuricemia in patients with gout ( Hair et al, 2008 ; Kamel et al, 2017 ; Robinson and Dalbeth, 2018 ). In addition to the treatment of gout, febuxostat played roles in preventing the progression of periodontitis ( Nessa et al, 2021 ), preventing the cytotoxicity of propofol in brain endothelial cells ( Hao et al, 2021 ), attenuating testosterone-induced benign prostatic hyperplasia ( Abdel-Aziz et al, 2020 ), ameliorating methotrexate-induced lung damage ( Zaki et al, 2021 ), and mitigating concanavalin A-induced acute liver injury ( Maresh et al, 2020 ) in animal experiments. Moreover, febuxostat suppressed renal ischemia-reperfusion injury by modulating oxidative stress and promoting the resynthesis of adenine nucleotides ( Tsuda et al, 2012 ; Fujii et al, 2019 ).…”