A Novel Class of Dual-Acting DCH-CORMs Counteracts Oxidative Stress-Induced Inflammation in Human Primary Tenocytes.

Marialucia Gallorini,Simone Carradori,Giovanna Poce,Arianna Granese,Federico Appetecchia,Sara Consalvi,Mariangela Biava,Cristina Campestre,Emanuela Berrino

doi:10.3390/antiox10111828

Marialucia Gallorini, Simone Carradori + Show 7 more

Open Access

https://doi.org/10.3390/antiox10111828

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Abstract

Carbon monoxide (CO) can prevent cell and tissue damage by restoring redox homeostasis and counteracting inflammation. CO-releasing molecules (CORMs) can release a controlled amount of CO to cells and are emerging as a safer therapeutic alternative to delivery of CO in vivo. Sustained oxidative stress and inflammation can cause chronic pain and disability in tendon-related diseases, whose therapeutic management is still a challenge. In this light, we developed three small subsets of 1,5-diarylpyrrole and pyrazole dicobalt(0)hexacarbonyl (DCH)-CORMs to assess their potential use in musculoskeletal diseases. A myoglobin-based spectrophotometric assay showed that these CORMs act as slow and efficient CO-releasers. Five selected compounds were then tested on human primary-derived tenocytes before and after hydrogen peroxide stimulation to assess their efficacy in restoring cell redox homeostasis and counteracting inflammation in terms of PGE2 secretion. The obtained results showed an improvement in tendon homeostasis and a cytoprotective effect, reflecting their activity as CO-releasers, and a reduction of PGE2 secretion. As these compounds contain structural fragments of COX-2 selective inhibitors, we hypothesized that such a composite mechanism of action results from the combination of CO-release and COX-2 inhibition and that these compounds might have a potential role as dual-acting therapeutic agents in tendon-derived diseases.

Highlights

The carbon monoxide (CO) releasing behaviors of compounds 1–9 were evaluated through a myoglobin (Mb)-based spectrophotometric assay, considered the gold standard to analyze the CO releasing kinetics and a key criterion to select CO-releasing molecules (CORMs) structures [17,31]
This method analyzes the release of CO from CORMs by following the conversion of deoxymyoglobin (deoxy-Mb(II)) into CO-myoglobin (CO-Mb(II)) over time by UV-Vis spectroscopy
We developed a novel series of DCH-CORMs based on a 1,5-diarylpyrrole scaffold

Summary

Introduction

CO-releasing molecules (CORMs) can release carbon monoxide (CO) either spontaneously, enzymatically, or triggered by an external stimulus [1]. Their therapeutic potential relies on the release of a limited amount of CO. The expression of the HO inducible isoform (HO-1) is triggered by cell responses toward oxidative stress and inflammation and results in cyto- and tissue protection. The manipulation of the HO-1/CO system is an attractive strategy to treat conditions linked to oxidative-stress-induced inflammation, such as lung hyper-inflammation in cystic fibrosis, sepsis and modulation of chronic pain [2,3,4,5,6,7].

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