Protective effect of soloxolone derivatives in carrageenan- and LPS-driven acute inflammation: Pharmacological profiling and their effects on key inflammation-related processes

• Published in: Biomedicine & pharmacotherapy 2023-03, Vol.159, p.114231-114231, Article 114231
• Main Authors: Sen’kova, Aleksandra V., Savin, Innokenty A., Odarenko, Kirill V., Salomatina, Oksana V., Salakhutdinov, Nariman F., Zenkova, Marina A., Markov, Andrey V.
• Format: Article
• Language: English
• Subjects: Acute lung injury; Animals; Anti-Inflammatory Agents; Apoptosis; Carrageenan; Carrageenan - therapeutic use; Cyanoenone-bearing triterpenoids; Edema - chemically induced; Edema - drug therapy; Epithelial-mesenchymal transition; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Lipopolysaccharides; Mice; Peritonitis - drug therapy; Soloxolone methyl; Thrombin
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114231

The anti-inflammatory potential of three cyanoenone-containing triterpenoids, including soloxolone methyl (SM), soloxolone (S) and its novel derivative bearing at the C-30 amidoxime moiety (SAO), was studied in murine models of acute inflammation. It was found that the compounds effectively suppressed the development of carrageenan-induced paw edema and peritonitis as well as lipopolysaccharide (LPS)-driven acute lung injury (ALI) with therapeutic outcomes comparable with that of the reference drugs indomethacin and dexamethasone. Non-immunogenic carrageenan-stimulated inflammation was more sensitive to the transformation of C-30 of SM compared with immunogenic LPS-induced inflammation: the anti-inflammatory properties of the studied compounds against carrageenan-induced paw edema and peritonitis decreased in the order of SAO > S > > SM, whereas the efficiency of these triterpenoids against LPS-driven ALI was similar (SAO ≈ S ≈ SM). Further studies demonstrated that soloxolone derivatives significantly inhibited a range of immune-related processes, including granulocyte influx and the expression of key pro-inflammatory cytokines and chemokines in the inflamed sites as well as the functional activity of macrophages. Moreover, SM was found to prevent inflammation-associated apoptosis of A549 pneumocytes and effectively inhibited the protease activity of thrombin (IC50 = 10.3 µM) tightly associated with rodent inflammatome. Taken together, our findings demonstrate that soloxolone derivatives can be considered as novel promising anti-inflammatory drug candidates with multi-targeted mechanism of action. [Display omitted] •Soloxolone derivatives (SDs) effectively ameliorate carrageenan-induced inflammation and LPS-stimulated ALI in mice.•SDs suppress the expression of key inflammatory genes in inflamed sites and the functional activity of murine macrophages.•SDs inhibit macrophage NO production by both suppression of Nos2 expression and probable direct interaction with iNOS.•Soloxolone methyl (SM) displays cytoprotective effect on inflamed pneumocytes and does not affect their ALI-driven EMT.•SM directly inhibits the activity of thrombin involved in the regulation of inflammation.