A novel diselenide attenuates the carrageenan-induced inflammation by reducing neutrophil infiltration and the resulting tissue damage in mice

Abstract

Selenium-containing compounds have emerged as promising treatment for redox-based and inflammatory diseases. This study aimed to investigate the in vitro and in vivo anti-inflammatory activity of a novel diselenide named as dibenzyl[diselanediyIbis(propane-3-1diyl)] dicarbamate (DD). DD reacted with HOCl (k = 9.2 x 10⁷ M⁻¹s⁻¹), like glutathione (k = 1.2 x 10⁸ M⁻¹s⁻¹), yielding seleninic and selenonic acid derivatives, and it also decreased HOCl formation by activated human neutrophils (IC₅₀=4.6 μM) and purified myeloperoxidase (MPO) (IC₅₀=3.8 μM). However, tyrosine, MPO-I and MPO-II substrates, did not restore HOCl formation in presence of DD. DD inhibited the oxidative burst in dHL-60 cells with no toxicity up to 25 µM for 48h. Next, an intraperitoneal administration of 25, 50, and 75 mg/kg DD decreased total leukocyte, neutrophil chemotaxis, and inflammation markers (MPO activity, lipid peroxidation, albumin exudation, nitrite, TNF-α, IL-1β, CXCL1/KC, and CXCL2/MIP-2) on a murine model of carrageenan-induced peritonitis. Likewise, 50 mg/kg DD (i.p.) decreased carrageenan-induced paw edema over 5h. Histological and immunohistochemistry analyses of the paw tissue showed decreased neutrophil count, edema area, and MPO, carbonylated, and nitrated protein staining. Furthermore, DD treatment decreased the fMLP-induced chemotaxis of human neutrophils (IC₅₀=3.7 μM) in vitro with no toxicity. Lastly, DD presented no toxicity in a single-dose model using mice (50 mg/kg, i.p.) over 15 days and in Artemia salina bioassay (50 to 2000 µM), corroborating findings from in silico toxicological study. Altogether, these results demonstrate that DD attenuates carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting damage from MPO-mediated oxidative burst.

Keywords:

• Selenium
• inflammation
• oxidative burst
• neutrophil chemotaxis
• myeloperoxidase
• hypochlorous acid

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors thank Fundação de Amparo à Pesquisa da Bahia (FAPESB) (BOL0286/2017), Universidade Estadual do Sudoeste da Bahia (AUXPPG TO005/2019; AUXPPG TO06/2022; AUXPPI TO042/2022), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (JP-2, 2018/14898-2; CEPID Redoxoma, 2013/07937-8; 2019/07634-1; 2015/08539-1; 2019/25634-9; 2021/06726-0), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) (financing code – 001), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (305858/2020-3) for the financial support.