Protective effect of soloxolone derivatives in carrageenan- and LPS-driven acute inflammation: Pharmacological profiling and their effects on key inflammation-related processes - 03/02/23
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | 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. |
Keywords : Inflammation, Soloxolone methyl, Cyanoenone-bearing triterpenoids, Carrageenan, Acute lung injury, Epithelial-mesenchymal transition, Apoptosis, Thrombin
Plan
Vol 159
Article 114231- mars 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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