RESUMO
Cardiomyopathy related to the absence of dystrophin is an important feature in Duchenne muscular dystrophy (DMD) and in the mdx mouse. Doxycycline (DOX) could be a potential therapy for mdx skeletal muscles dystrophy. We investigated whether the corticoid deflazacort (DFZ) plus DOX could improve cardiac mdx dystrophy better than DFZ alone, later (17 months) in dystrophy. Mdx mice (8 months old) received DFZ/DOX or DFZ for 9 months. The combined therapy was greater than DFZ in reducing fibrosis (60% decrease with DFZ/DOX and 40% with DFZ alone) in the right ventricle and transforming growth factor ß levels (6.8 ± 3.2 in untreated mdx mice, 2.8 ± 1.4 in combined therapy, and 4.6 ± 1.7 in DFZ; P < .05). Combined therapy more effectively ameliorated cardiac dysfunction (electrocardiogram [ECG]) than DFZ. Improvements were seen in the cardiomyopathy index (0.8 ± 0.1 in combined therapy and 1.0 ± 0.2 in DFZ), heart rate (418 ± 46 bpm in combined therapy and 457 ± 29 bpm in DFZ), QRS interval (11.3 ± 2 in combined therapy and 13.6 ± 1 in DFZ), and Q wave amplitude (-40.7 ± 21 in combined therapy and -90.9 ± 36 in DFZ). Both therapies decreased markers of inflammation (tumor necrosis factor α, nuclear factor κB, and metalloproteinase 9). DFZ/DOX improved mdx cardiomyopathy at this stage of the disease, supporting further clinical investigations.
Assuntos
Cardiomiopatias/tratamento farmacológico , Doxiciclina/administração & dosagem , Distrofina/deficiência , Distrofia Muscular de Duchenne/complicações , Pregnenodionas/uso terapêutico , Animais , Cardiomiopatias/etiologia , Doxiciclina/toxicidade , Quimioterapia Combinada , Eletrocardiografia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pregnenodionas/administração & dosagem , Pregnenodionas/toxicidadeRESUMO
Prednisone (PDN) impairs cognitive functioning and brain structures in humans and animals. Deflazacort (DFZ) is a synthetic glucocorticoid claimed to have lesser side effects than prednisone. The objective of this study was to assess whether chronic administration (90 days) of DFZ produces less neuronal degeneration and glial reactivity than PDN. Male Swiss-Wistar rats were studied. Controls received 0.1 ml distilled water orally. The PDN group received prednisone 5 mg per kg per day orally, and the DFZ group received deflazacort 6 mg per kg per day orally. This model had to be assembled in three different occasions due to excess mortality in the DFZ group. A fourth model was assembled using only the DFZ group and slides of water and PDN-exposed rats from a previous study were used as comparators. The index of degenerated neurons and the number and cytoplasmic transformation of astrocytes and microglia cells were evaluated in the prefrontal cortex, CA1, and CA3 hippocampus. The results show that the overall mortality was 49% in the DFZ group, 4.5% in the PDN group, and none of the controls died. Routine necropsy showed infection in multiple organs. The PDN group had two times higher neuronal degeneration in the prefrontal cortex, almost 11 times in CA1, and four times in CA3 hippocampus when compared with controls and DFZ group. Astrocytes reactivity was increased in the PDN- and DFZ-exposed rats compared with controls. The DFZ group showed an average of four times less microgial cells in the three studied regions when compared with controls and the PDN group. In conclusion, it seems that DFZ at the equivalent licensed dose produced a stronger immunosuppressive effect--systemic and in brain tissue--than PDN, but induced less neuronal damage. The immunosuppressant magnitude of DFZ should be further studied in clinical settings.