Beneficial Effects of Two Hydrogen Sulfide (H2S)-Releasing Derivatives of Dexamethasone with Antioxidant Activity on Atopic Dermatitis in Mice

Abstract

Hydrogen sulfide (H2S) is particularly produced in the skin, where it participates in the regulation of inflammation, pruritus, cytoprotection, scarring, and angiogenesis. In this study, we compared the effects of dexamethasone (Dex) with two H2S-releasing Dex derivatives in a murine model of atopic dermatitis (AD) induced by topical application of 2,4-dinitrochlorobenzene (DNCB). After sensitization with DNCB, the animals were topically treated for five consecutive days with either the H2S-releasing compounds 4-hydroxy-thiobenzamide (TBZ) and 5-(p-hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), Dex, or the derivatives Dex-TBZ or Dex-ADT. Topical treatment with equimolar doses of either Dex, Dex-TBZ, or Dex-ADT resulted in similar reductions in dermatitis score, scratching behavior, edema, eosinophilia, splenomegaly, and histological changes. In contrast with Dex, the H2S-releasing derivatives prevented IL-4 elevation and oxidative modification of skin proteins. On an equimolar dose basis, Dex-TBZ, but not Dex-ADT, promoted the elevation of endogenous H2S production and GPx activity. Neither Dex-TBZ nor Dex-ADT decreased GR activity or caused hyperglycemia, as observed with Dex treatment. We conclude that the presence of H2S-releasing moieties in the Dex structure does not interfere with the anti-inflammatory effects of this corticosteroid and adds beneficial therapeutical actions to the parent compound.

Mechanistic Intimate Insights into the Role of Hydrogen Sulfide in Alzheimer’s Disease: A Recent Systematic Review

“…For instance, compounds like GYY4137 gradually release H 2 S, enhancing its neuroprotective and anti-inflammatory effects [89,141]. Furthermore, hybrid drugs combine NSAIDs' anti-inflammatory attributes with H 2 S release, targeting dual therapeutic outcomes for AD [92]. Balneotherapeutic methods using sulfurous mineral waters and mud therapy also increase plasma H 2 S levels [131,142].…”

“…Slow-releasing H 2 S donors, like GYY4137 [89,90], which are agents that can upregulate the activity or expression of H 2 S-producing enzymes, can elevate brain H 2 S levels, bolstering the direct and indirect antioxidative mechanisms to counteract oxidative stress in AD [91]. Also, the development of hybrid molecules that can release H 2 S and also possess intrinsic antioxidant activity can offer a dual antioxidative thrust, potentially yielding synergistic benefits in quelling oxidative stress in AD [92,93].…”