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| Author(s): |
Silvia Abigail Coavoy Sanchez
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2021-04-12 |
| Examining board members: |
Marcelo Nicolas Muscara;
Edson Antunes;
Maria Martha Campos;
Wothan Tavares de Lima
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| Advisor: | Marcelo Nicolas Muscara |
| Abstract | |
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus and eczematous skin lesions, associated with enhanced T-helper-2 lymphocyte response. Corticosteroids are commonly used as anti-inflammatory therapy for AD, however, long-term treatment is limited due to several side-effects, thus making necessary the development of alternative therapies. Hydrogen sulfide (H2S) is produced in the skin and its beneficial effects on the control of inflammation and pruritus have been demonstrated. In this study, we used a murine model of AD induced by 2,4-dinitrochlorobenzene (DNCB) and evaluated the effects of H2S releasing dexamethasone derivative compounds (hybrids with thiobenzamide - TBZ and anethole dithiolethione - ADT) and the mitochondria-targeted H2S donors AP39 and RT01. Female BALB/c mice were topically sensitized with DNCB on days 1-3. On days 15, 17, 19 and 22, the mice were topically challenged with DNCB on both the dorsal skin and the right ear. On days 19-23 after sensitization, the mice were topically treated with 250 nmol/mice dexamethasone or its derivatives, or 0.2 nmol/mice AP39 or RT01. Topical treatment with dexamethasone and its derivatives significantly reduced itching, skin severity score, ear edema, eosinophilia and splenomegaly induced by DNCB. Treatment with dexamethasone-TBZ or dexamethasone-ADT, but not dexamethasone, inhibited IL-4 levels, and treatment with dexamethasone-TBZ (but not with dexamethasone or dexamethasone-ADT), increased the production of H2S and the activity of glutathione peroxidase (GPx) in the skin. Both dexamethasone-TBZ and dexamethasone-ADT, but not dexamethasone, inhibited the increased oxidative stress markers nitrotyrosine and carbonylated proteins induced by DNCB. In addition, while dexamethasone induced hyperglycemia, dexamethasone-TBZ and dexamethasone-ADT prevented this effect. On the other hand, treatment with TBZ or ADT-OH decreased eosinophilia, and reduced the increased levels of IL-4 and the enzyme alanine aminotransferase (ALT), induced by DNCB. Topical treatment with AP39 reduced itching, skin severity score, ear edema, eosinophilia and splenomegaly induced by DNCB. AP39 reduced IL-4, eotaxin-1 and carbonylated proteins levels which are increased in the skin of the AD mice. On the other hand, treatment with RT01 resulted in a reduction of skin severity score, eosinophilia and IL-4 levels. These results show that the presence of H2S releasing portions (TBZ or ADT) in the dexamethasone molecule, not only does not interfere with the beneficial effects of the corticosteroid, but also adds benefits to the parental molecule, such as the increased activity of antioxidant defenses in the treatment of AD and prevention of hyperglycemia associated with corticosteroids. On the other hand, the specific delivery of H2S in the mitochondria by the compound AP39, can suppress the clinical signs of AD via immune modulation and maintenance of redox balance. In summary, the compounds evaluated in this work configure interesting strategies for the potential therapeutic application in the treatment of patients with AD. (AU) | |
| FAPESP's process: | 17/16409-6 - Effect of hydrogen sulfide (H2S) donors on experimental atopic dermatitis in mice. |
| Grantee: | Silvia Abigail Coavoy Sanchez |
| Support Opportunities: | Scholarships in Brazil - Doctorate |