Loganin Alleviates Gout Inflammation by Suppressing NLRP3 Inflammasome Activation and Mitochondrial Damage

Abstract

Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for a small-molecule inhibitor of the NLRP3 inflammasome for the prevention of gout inflammation. We found that loganin suppressed MSU crystals-induced caspase-1 (p20) and interleukin (IL)-1β production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks formation in mouse primary macrophages, showing its ability to inhibit the NLRP3 inflammasome. In an air pouch inflammation model, oral administration of loganin to mice prevented MSU crystals-induced production of mature IL-1β and IL-18 in air pouch exudates, resulting in decreased neutrophil recruitment. Furthermore, oral administration of loganin suppressed MSU crystals-induced gout inflammation in a mouse foot gout model, which was accompanied by the inhibition of the NLRP3 inflammasome. Loganin blocked de novo synthesis of mitochondrial DNA in air pouches and foot tissues injected with MSU crystals. Consistently, loganin prevented MSU crystals-induced mitochondrial damage in macrophages, as it increased mitochondrial membrane potential and decreased the amount of mitochondrial reactive oxygen species. These data demonstrate that loganin suppresses NLRP3 inflammasome activation by inhibiting mitochondrial stress. These results suggest a novel pharmacological strategy to prevent gout inflammation by blocking NLRP3 inflammasome activation and mitochondrial dysfunction.

Carvacrol Alleviates Hyperuricemia-Induced Oxidative Stress and Inflammation by Modulating the NLRP3/NF-κB Pathwayt

“…58 , 59 Therefore, directly targeting NLRP3 and its associated factors or proteins may effectively inhibit NLRP3 activation and potentially produce benefits in gout treatment. 60 Previous clinical trials utilizing different drugs that target only a single step in a specific disorder have failed. However, in this study, carvacrol ameliorated the detrimental effects of hyperuricemia by targeting multiple stages, including inflammation, oxidative stress, and cellular degeneration.…”

The Protective Effects of Neoastilbin on Monosodium Urate Stimulated THP-1-Derived Macrophages and Gouty Arthritis in Mice through NF-κB and NLRP3 Inflammasome Pathways

“…In the present study, neoastilbin inhibited GA, including inflammatory cytokine release and inflammatory cell infiltration into the lesion site, mediated by the suppression of NF-κB and NLRP3 inflammasome pathways in THP-1-derived macrophages and GA mice. Considering that the NF-κB and NLRP3 inflammasome pathways are related to the development of many inflammatory diseases, neoastilbin may have potential clinical application value in gout, autoinflammatory syndrome or other NLRP3-driven diseases [ 41 , 42 , 43 , 44 ].…”

Phytochemistry, synthesis, analytical methods, pharmacological activity, and pharmacokinetics of loganin: A comprehensive review

“…The inflammasomes can promote the cleavage of pro‐IL‐1β and pro‐IL‐18 into mature IL‐1β and IL‐18, which in turn induces the death of inflammatory cells. It has been shown that loganin can reduce gouty arthritis by inhibiting the activation of NLRP3 inflammasomes and mitochondrial dysfunction (Choi et al, 2021).…”