NLRP3 inflammasome inhibition attenuates subacute neurotoxicity induced by acrylamide in vitro and in vivo

[Display omitted] •NLRP3 inflammasome activation contributes to acrylamide-induced neurotoxicity.•The NLRP3 inflammasome blocker MCC950 or NLRP3 knockout mice alleviate acrylamide poisoning.•NLRP3 inflammasome antagonism protects against acrylamide poisoning via two main mechanisms. Acrylamide (AA) constitutes an important industrial chemical agent and well-known neurotoxin. However, the mechanism underlying AA-mediated neurotoxicity is extremely complicated and controversial. In this study, we found that activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and its subsequent downstream inflammatory responses plays an important role in AA-induced neurotoxicity mechanisms. In vitro experiments revealed that AA (2.5 mM) induced BV2 microglial cytotoxicity and triggered NLRP3 inflammasome activation along with downstream proinflammatory cytokine interleukin-1β and interleukin-18 expression. Treatment with inhibitor or NLRP3 siRNA efficiently protected BV2 microglial cells against AA-induced cytotoxicity and reversed NLRP3 inflammasome activation and its mediated inflammatory reaction. Similarly, AA exposure (50 mg/kg) for 10 consecutive days caused significant activation of NLRP3 inflammasomes and neuroinflammation in C57BL/6 mice, whereas inhibiting these effects through specific NLRP3 inflammasome blocker MCC950 (5 mg/kg) intervention or NLRP3 knock-out significantly ameliorated AA-induced ataxia, cerebellar Purkinje cells degeneration, and apoptosis. Furthermore, we demonstrated that antagonism of NLRP3 could also up-regulate the Nrf2 signalling pathway and related antioxidant genes. In conclusion, our findings indicate that activation of the NLRP3 inflammasome pathway is involved in AA-induced neurotoxicity, whereas MCC950 treatment or NLRP3 knock-out could effectively protect against AA-induced neurotoxic injury through the inhibition of neuroinflammation and activation of the Nrf2 antioxidant pathway. Therefore, the NLRP3 inflammasome might serve as a promising therapeutic target, with drugs designed to specifically inhibit this pathway potentially providing new avenues for preventing or ameliorating AA poisoning.