The
nucleotide-binding domain and
leucine-rich repeat protein 3 (NLRP3), an intracellular signaling molecule that senses many environmental- and pathogen/host-derived factors, has been implicated in the pathogenesis of several diseases associated with
inflammation. It has been suggested that NLRP3
inflammasome inhibitors may have a therapeutic potential in the treatment of NLRP3-related inflammatory diseases. The aim of this study was to determine whether inhibition of NLRP3
inflammasome prevents inflammatory
hyperalgesia induced by
lipopolysaccharide (LPS) in mice as well as changes in expression/activity of nuclear factor κB (NF-κB),
caspase-1/11,
nicotinamide adenine dinucleotide phosphate oxidase (NOX), and endothelial/neuronal/
inducible nitric oxide synthase (eNOS/nNOS/iNOS) that may regulate NLRP3/apoptosis-associated speck-like
protein containing a caspase recruitment domain (ASC)/
pro-caspase-1 inflammasome formation and activity by using a selective NLRP3
inflammasome inhibitor,
MCC950. Male mice received saline (10 ml/kg; i.p.), LPS (10 mg/kg; i.p.), and/or
MCC950 (3 mg/kg; i.p.). Reaction time to thermal stimuli within 1 min was evaluated after 6 h. The mice were killed and the brains, hearts, and lungs were collected for measurement of NF-κB, caspase-1, caspase-11, NLRP3, ASC, NOX subunits (gp91phox; NOX2), and p47phox; NOXO2),
nitrotyrosine, eNOS, nNOS, iNOS, and β-actin
protein expression, NOS activity, and
interleukin (IL)-1β levels. LPS-induced
hyperalgesia was associated with a decrease in eNOS, nNOS, and iNOS
protein expression and activity as well as an increase in expression of NF-κB p65,
caspase-1 p20,
caspase-11 p20, NLRP3, ASC, gp91phox, p47phox, and
nitrotyrosine proteins in addition to elevated IL-1β levels. The LPS-induced changes were prevented by
MCC950. The results suggest that inhibition of NLRP3/ASC/
pro-caspase-1 inflammasome formation and activity prevents inflammatory
hyperalgesia induced by LPS in mice as well as changes in NF-κB,
caspase-11, NOX2, NOXO2, and eNOS/nNOS/iNOS expression/activity.