NU9056, a KAT 5 Inhibitor, Treatment Alleviates Brain Dysfunction by Inhibiting NLRP3 Inflammasome Activation, Affecting Gut Microbiota, and Derived Metabolites in LPS-Treated Mice

Abstract

Background: The pathogenesis of sepsis-associated encephalopathy (SAE) is complicated, while the efficacy of current treatment technologies is poor. Therefore, the discovery of related targets and the development of new drugs are essential.Methods: A mouse model of SAE was constructed by intraperitoneal injection of lipopolysaccharide (LPS). LPS treatment of microglia was used to build an in vitro model of inflammation. Nine-day survival rates, behavioral testing, transmission electron microscopy (TEM), immunohistochemical (IHC), immunofluorescence (IF), and ELISA were performed. The expression levels of Occludin, Claudin 5, NLRP3, caspase-1, and ASC genes and proteins were detected by RT-qPCR or Western blot. Caspase-1 P10 (Casp-1 P10) protein expression was detected. 16S rDNA sequencing and gas chromatography-mass spectrometer (GC-MS) were used to analyze the gut microbiota and metabolism. Flow cytometric experiment and Cell Counting Kit-8 (CCK8) assay were performed.Results: NU9056 improved the survival rate of mice and alleviated LPS-induced cognitive impairment, anxiety, and depression in vivo. The tight junctions were thickened via NU9056 treatment. Further, the mRNAs and proteins expression levels of Occludin and Claudin 5 were up-regulated by NU9056. NU9056 increased the expression level of DCX. The expression levels of Iba-1, NLRP3, IL-1β, ASC, and Casp-1 P10 were down-regulated by NU9056. The composition of the gut microbiota changed. Kyoto Encyclopedia of Genes and Genomes data predicted that the effects of NU9056 might be related to apoptosis and tight junction pathways. NU9056 up-regulated the concentration of acetate, propionate, and butyrate. NU9056 significantly reduced LPS-induced apoptosis of microglia, the average fluorescence intensity of ROS, and the release of IL-1β and IL-18, while improving cell viability in vitro.Conclusions: NU9056 might effectively alleviate LPS-induced cognitive impairment and emotional disorder in experimental mice by inhibiting the NLRP3 inflammasome. The therapeutic effects may be related to gut microbiota and derived metabolites. NU9056 might be a potential drug of SAE prevention.

Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice

“…In previous studies, FMT, probiotics, or certain drugs were shown to alleviate SAE by affecting the intestinal microbiota ( 18 , 24 ). These studies indicated that the gut microbiota may be an upstream regulator of SAE, which is consistent with our findings.…”

Targeting the gut microbiome in the management of sepsis-associated encephalopathy

“…Concentration changes of these endogenous microflora observed in sepsis lead to the progression of altered mentation and have substantial impacts on CNS function. The reduction in SCFA production from gut microflora during sepsis increases inflammatory markers, endotoxins due to the inability to downregulate inflammation ( 20 ) ( Figure 2 ).…”

“…Limited evidence is now available for the use of prebiotics, probiotics, fecal microbiota transplantation, and Vagus nerve stimulation for the treatment and prevention of SAE. Several investigational therapies demonstrating neuroprotective benefits, including palmitoylethanolamide, KAT5 inhibitors, capsase-1 inhibitors and butyrate supplementation for SAE remain in the therapeutic pipeline ( 20 , 47 , 48 ). Dexmedetomidine exhibits anti-inflammatory effects in vitro and its potential therapeutic benefit in the setting of SAE being actively investigated in the Adjunctive Sedation With Dexmedetomidine for the Prevention of Severe Inflammation and Septic Encephalopathy (ADVISE) trial ( 49 ).…”

Possible role of the NLRP3 inflammasome and the gut–brain axis in multiple sclerosis‐related depression

“…A recent study conducted by Chen et al found that selective inhibitor of KAT5 histone acetyltransferase (NU9056), an enzyme which is associated with inhibition of the NLRP3 inflammasome, alleviated LPS‐induced cognitive impairment, depressive and anxiety behaviors, and the release of pro‐inflammatory IL‐1β and IL‐18 cytokines in vitro. Also, it also improved BBB permeability and expression of doublecortin (DCX), a marker of newborn neurons, in mouse model of sepsis‐associated encephalopathy (SAE), by inhibiting NLRP3 activity 114 . According to research findings, NU9056 enhanced survivability in animals, ameliorated LPS‐induced cognitive impairment, depression, and anxiety‐like behavior in vivo.…”