7 research outputs found
Exon Skipping and Myoblast Transplantation: Single or Combined Potential Options for Treatment of Duchenne Muscular Dystrophy
Evaluation of potential synergistic action of a combined treatment with alpha-methyl-prednisolone and taurine on the mdx mouse model of Duchenne muscular dystrophy
Aims: Glucocorticoids are the sole drugs clinically used in Duchenne muscular dystrophy, in spite of the relevant side effects. Combination of glucocorticoids with synergistic drugs may be one strategy to lower doses and control side effects, meanwhile providing wider control of the complex pathology. This study is a preclinical evaluation of the effect of a combined treatment of amethyl-prednisolone (PDN) with taurine, a safe aminoacid with positive effects on some pathology-related events. Methods: PDN (1 mg/kg/day i.p.) and taurine (1 g/kg/day orally) were administered either alone or in combination, for 4-8 weeks to male dystrophic mdx mice chronically exercised on a treadmill. Effects were assessed in vivo and ex vivo with a variety of methodological approaches. Results: In vivo, each treatment significantly increased fore limb strength, a marked synergistic effect being observed with the combination PDN + taurine. Ex vivo, PDN + taurine completely restored the mechanical threshold, an electrophysiological index of calcium homeostasis, of extensor digitorum longus myofibres and the benefit was greater than for PDN alone. In parallel, the overactivity of voltage-independent cation channels in dystrophic myofibres was reduced. No effects were observed on plasma levels of creatine kinase, while lactate dehydrogenase was decreased by taurine and, to a minor extent, by PDN + taurine. A similar histology profile was observed in PDN and PDN + taurine-treated muscles. PDN + taurine significantly increased taurine level in fast-twitch muscle and brain, by high-pressure liquid chromatography analysis. Conclusions: The combination PDN + taurine has additive actions on in vivo and ex vivo functional end points, with less evident advantages on histopathology and biochemical markers of the disease
Exon Skipping and Myoblast Transplantation: Single or Combined Potential Options for Treatment of Duchenne Muscular Dystrophy
15+ MILLION TOP 1% MOST CITED SCIENTIST 12.2% AUTHORS AND EDITORS FROM TOP 500 UNIVERSITIES Exon Skipping and Myoblast Transplantation: Single or Combined Potential Options for Treatment of Duchenne Muscular Dystrophy
Effects of prednisolone on the dystrophin-associated proteins in the blood-brain barrier and skeletal muscle of dystrophic mdx mice.
Effects of prednisolone on the dystrophin-associated proteins in the blood-brain barrier and skeletal muscle of dystrophic mdx mice.
The mdx mouse, the most widely used animal model of Duchenne muscular dystrophy
(DMD), develops a seriously impaired blood-brain barrier (BBB). As
glucocorticoids are used clinically to delay the progression of DMD, we evaluated
the effects of chronic treatment with α-methyl-prednisolone (PDN) on the
expression of structural proteins and markers in the brain and skeletal muscle of
the mdx mouse. We analyzed the immunocytochemical and biochemical expression of
four BBB markers, including endothelial ZO-1 and occludin, desmin in pericytes,
and glial fibrillary acidic protein (GFAP) in glial cells, and the expression of
the short dystrophin isoform Dp 71, the dystrophin-associated proteins (DAPs),
and aquaporin-4 (AQP4) and α-β dystroglycan (DG) in the brain. We evaluated the
BBB integrity of mdx and PDN-treated mdx mice by means of intravascular injection
of horseradish peroxidase (HRP). The expression of DAPs was also assessed in
gastrocnemius muscles and correlated with utrophin expression, and laminin
content was measured in the muscle and brain. PDN treatment induced a significant
increase in the mRNA and protein content of the BBB markers; a reduction in the
phosphorylation of occludin in the brain and of AQP4/β DG in both tissues; an
increase of Dp71 protein content; and an increase of both mRNA and protein levels
of the AQP4/α-β DG complex. The latter was associated with enhanced laminin and
utrophin in the muscle. The HRP assay demonstrated functional restoration of the
BBB in the PDN-treated mdx mice. Specifically, mdx mice showed extensive
perivascular labeling due to escape of the marker, while HRP was exclusively
intravascular in the PDN-treated mice and the controls. These data illustrate for
the first time that PDN reverses the BBB alterations in the mdx mouse and
re-establishes the proper expression and phosphorylation of β-DG in both the BBB
and skeletal muscle. Further, PDN partially protects against muscle damage. The
reduction in AQP4 and occludin phosphorylation, coupled with their anchoring to
glial and endothelial membranes in PDN-treated mice, suggests that the drug may
target the glial and endothelial cells. Our results suggest a novel mechanism for
PDN action on cerebral and muscular function, restoring the link between DAPs and
the extracellular matrix, most likely through protein kinase inactivation