[Ru(bpy)2(NO)SO3](PF6), a Nitric Oxide Donating Ruthenium Complex, Reduces Gout Arthritis in Mice

Abstract

Monosodium urate crystals (MSU) deposition induces articular inflammation known as gout. This disease is characterized by intense articular inflammation and pain by mechanisms involving the activation of the transcription factor NFκB and inflammasome resulting in the production of cytokines and oxidative stress. Despite evidence that MSU induces iNOS expression, there is no evidence on the effect of nitric oxide (NO) donors in gout. Thus, the present study evaluated the effect of the ruthenium complex donor of NO {[Ru(bpy)2(NO)SO3](PF6)} (complex I) in gout arthritis. Complex I inhibited in a dose-dependent manner MSU-induced hypersensitivity to mechanical stimulation, edema and leukocyte recruitment. These effects were corroborated by a decrease of histological inflammation score and recruitment of Lysm-eGFP+ cells. Mechanistically, complex I inhibited MSU-induced mechanical hypersensitivity and joint edema by triggering the cGMP/PKG/ATP-sensitive K (+) channels signaling pathway. Complex I inhibited MSU-induced oxidative stress and pro-inflammatory cytokine production in the knee joint. These data were supported by the observation that complex I inhibited MSU-induced NFκB activation, and IL-1β expression and production. Complex I also inhibited MSU-induced activation of pro-IL-1β processing. Concluding, the present data, to our knowledge, is the first evidence that a NO donating ruthenium complex inhibits MSU-induced articular inflammation and pain. Further, complex I targets the main physiopathological mechanisms of gout arthritis. Therefore, it is envisaged that complex I and other NO donors have therapeutic potential that deserves further investigation.

RETRACTED: NFIL3 Facilitates Neutrophil Autophagy, Neutrophil Extracellular Trap Formation and Inflammation During Gout via REDD1-Dependent mTOR Inactivation

“…Gout is characterized by severe articular inflammation and pain induced by MSU deposition precipitated by activation of transcription factors ( 19 , 20 ). Pre-experimentation and confirmation findings in our study demonstrated that transcription factor NFIL3 promoted the transcription of REDD1, induced a subsequent inhibition of mTOR pathway, and enhanced the neutrophil autophagy and NET formation, consequently preventing the inflammatory response of gout.…”

Eucalyptol alleviates inflammation and pain responses in a mouse model of gout arthritis

“…MSU can trigger the release of some key pro‐inflammatory cytokines and chemokines, including IL‐6, TNF‐α, CXCL1, and CXCL2 (Rossaneis et al, ; Ryckman et al, ; Staurengo‐Ferrari et al, ). We proceeded to examine the effects of eucalyptol on expression of these cytokines and chemokines in ankle joint tissues, compared with theeffects of indomethacin.…”

Ruthenium-nitrosyl complexes as NO-releasing molecules, potential anticancer drugs, and photoswitches based on linkage isomerism

“…Antileishmanial 213,214 and anti-inflammatory (as caused by gout arthritis) 215 activities of cis-[Ru(L) 2 (SO 3 )(NO)](PF 6 ), where L = bipyridine, were also reported recently. Anti-asthmatic complexes, cis-[Ru(L 1 ) 2 (L 2 )(NO)](PF 6 ) 3 , where L 1 = 2,2′-bipyridine, L 2 = 2-methyl-1Himidazole, 216 and [Ru(NO)(L 1 )(L 2 )] 3+ , where L 1 = terpyridine, L 2 = 1,2-benzoquinone-diimine, 217 were recently reported as well.…”