Laquinimod inhibits MMP+ induced NLRP3 inflammasome activation in human neuronal cells.

ABSTRACT

Objective: Nod-like receptor protein 3 (NLRP3) inflammasome plays anessentialrole in neuroinflammation in the Parkinson's disease (PD) progression. Laquinimodis an immunomodulator that is clinically used for the treatment of multiple sclerosis. This study aims to investigate whether laquinimod possessesa protective effect against MPP+-induced NLRP3 activation.Materials and methods: In a variety of tests on human SH-SY5Y neuronal cells, 1-methyl-4-phenyl Pyridine (MPP+) was used to mimic the microenvironment of PD. Activation of NLRP3 inflammasome was measured by western blot analysis and enzyme linked immunosorbent assay (ELISA).Results: Laquinimod had a significant protective impact against MPP+-induced neurotoxicity. Our results demonstrate that laquinimod prevented MPP+-induced reduction of cell proliferation, the release of lactate dehydrogenase (LDH), and apoptosis. Importantly, treatment with laquinimod significantly inhibited the activation of the NLRP3 inflammasome by reducing the levels of its components, including NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase 1 (P10). Consistently, laquinimod prevented MPP+-induced secretions of interleukin 1ß (IL-1ß) and interleukin-18 (IL-18). Additionally, laquinimod also reduced the expression of other related factors, such as intracellular reactive oxygen species (ROS), NADPH oxidase 4 (NOX-4), thioredoxin-interacting protein (TxNIP). Furthermore, laquinimod prevented the reduction of sirtuin 1 (SIRT1) from MPP+ stimulation. Inhibition of SIRT1 abolished the protective effects of laquinimod against the activation of the NLRP3 inflammasome, suggesting the involvement of SIRT1 in this process.Conclusion: These findings suggest that laquinimod treatment might be a possible therapeutic strategy for neuroinflammation in PD.