Nucleotide-binding oligomerization domain
leucine rich repeat and pyrin domain-containing
protein 3 (NLRP3)
inflammasome is pivotal in maintaining intestinal homeostasis and sustaining enteric immune responses in the setting of
inflammatory bowel diseases. Drugs acting as NLRP3 blockers could represent innovative strategies for treatment of bowel
inflammation. This study was performed in rats with
dinitrobenzenesulfonic acid (
DNBS)-induced
colitis, to investigate how the direct blockade of NLRP3
inflammasome with an irreversible inhibitor (INF39) compares with
Ac-YVAD-cmk (YVAD,
caspase-1 inhibitor) and
anakinra (IL-1β receptor antagonist), acting downstream on NLRP3 signaling. Animals with
DNBS-
colitis received YVAD (3 mg/kg) or
anakinra (100 mg/Kg) intraperitoneally, and INF39 (25 mg/kg) or
dexamethasone (DEX, 1 mg/kg) orally for 6 days, starting on the same day of
colitis induction. Under
colitis, there was a
body weight decrease, which was attenuated by YVAD,
anakinra or INF39, but not DEX. All test drugs counteracted the increase in spleen weight. The colonic shortening and morphological colonic alterations associated with
colitis were counteracted by INF39,
anakinra and DEX, while YVAD was without effects. Tissue increments of
myeloperoxidase,
tumor necrosis factor and interleukin-1β were more effectively counteracted by INF39 and DEX, than YVAD and
anakinra. These findings indicate that: (1) direct inhibition of NLRP3
inflammasome with INF39 is more effective than caspase-1 inhibition or IL-1β receptor blockade in reducing systemic and bowel inflammatory alterations; (2) direct NLRP3 inhibition can be a suitable strategy for treatment of bowel
inflammation.