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

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

Journal

Biomedicine & Pharmacotherapy
ISSN: 1950-6007

Output data

Year: 2023, Volume: 159, Pages: 114231 Pages count : 1 DOI: 10.1016/j.biopha.2023.114231

Tags

Inflammation, Soloxolone methyl, Cyanoenone-bearing triterpenoids, Carrageenan, Acute lung injury, Epithelial-mesenchymal transition, Apoptosis, Thrombin

Authors

Sen’kova Aleksandra V. ¹ , Savin Innokenty A. ¹ , Odarenko Kirill V. ¹ , Salomatina Oksana V. ² , Salakhutdinov Nariman F. ² , Zenkova Marina A. ¹ , Markov Andrey V. ¹

Affiliations

1	Institute of Chemical Biology and Fundamental Medicine SB RAS
2	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian Branch of Russian Academy of Sciences

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.

Sen’kova A.V. , Savin I.A. , Odarenko K.V. , Salomatina O.V. , Salakhutdinov N.F. , Zenkova M.A. , Markov A.V.
Protective effect of soloxolone derivatives in carrageenan- and LPS-driven acute inflammation: Pharmacological profiling and their effects on key inflammation-related processes
Biomedicine & Pharmacotherapy. 2023. V.159. P.114231. DOI: 10.1016/j.biopha.2023.114231 WOS Scopus РИНЦ

Submitted:	Dec 21, 2022
Accepted:	Jan 8, 2023
Published online:	Jan 12, 2023

Web of science	WOS:000925124200001
Scopus	2-s2.0-85147101171
Elibrary	60808818
OpenAlex	W4316340109