NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

Abstract

Background: Primary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear. Methods: To investigate the potential role of NLRP3 inflammasome activation in the pathogenesis of PD, 30 female Kunming mice without pregnancy were used for experiments. The PD mouse model was constructed by 11 days of successive co-treatment with estradiol and oxytocin. MCC950, a potent and specific small-molecule inhibitor of the NLRP3 inflammasome, was used to treat PD mice. The disease level was assessed by the writhing response and hot water tail-flick test. The levels of prostaglandin E 2 (PGE 2) and prostaglandin F 2 alpha (PGF 2α) in the uterine tissues of mice were detected by ELISA. The expression levels of protein and cytokines, including NLRP3, cysteine aspartic acid-specific protease 1 (caspase-1), interleukin (IL)-1β, IL-18, nuclear factor kappa B (NF-κB) p65, phospho-NF-κB p65, and cyclooxygenase-2 (COX-2) were revealed by western blot analysis. Results: MCC950 greatly ameliorated the writhing response induced by the combination of oxytocin and estradiol, with an increasing length of tail-flick latency. MCC950 also significantly decreased the levels of PGF 2α and PGE 2 , and the expressions of NLRP3, caspase-1, IL-1β, IL-18, phospho-NF-κB p65, NF-κB p65, and COX-2 in the uterus. Conclusions: MCC950 markedly alleviated the pain and pathological damage in PD mice by inhibiting NLRP3 activation. The underlying mechanism may be related to hypoactive uterine inflammation via suppression of NLRP3 activation and the NF-κB/COX-2/PG pathway in uteruses of PD mice.

Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950

“…NLRP3 activation has recently been implicated in primary dysmenorrhea, a common gynecological disease among young women. In a mouse model of primary dysmenorrhea, intraperitoneal injection of MCC950 decreased uterine prostaglandin F2 a and prostaglandin E 2 and the expression of NLRP3, caspase-1, IL-1b, IL-18, phosphorylated-NF-kB p65, NF-kB p65, and cyclooxygenase-2 (Tang et al, 2020).…”

The Establishment of a Mouse Model of Recurrent Primary Dysmenorrhea

“…In recent years, many studies have been carried out focusing on the pathological mechanism of PD and tried to develop more drugs for PD treatment [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. One acknowledged mechanism is that the overproduction of uterine PGs causes myometrial hypercontractility, resulting in ischemia and hypoxia of the uterine muscle and pain [ 2 , 4 ].…”

The relationship between spino-pelvic alignment and primary dysmenorrhea

“…Several studies have investigated the importance of sagittal spino-pelvic alignment in spinal disorders such as lumbar spondylolisthesis ( 12 – 14 ), adolescent idiopathic scoliosis ( 15 – 18 ), and adult spinal deformity ( 19 , 20 ). At the same time, the research on the etiology of primary dysmenorrhea mainly focuses on uterine over contraction ( 21 ), vasoconstriction ( 22 , 23 ), inflammation and release of inflammatory mediators ( 24 , 25 ), brain Imaging and stimulation of pain fibers ( 26 – 29 ).…”