Biomaterial Database

Effects of prednisolone on the dystrophin-associated proteins in the blood-brain barrier and skeletal muscle of dystrophic mdx mice. 2013

Roberto Tamma, and Tiziana Annese, and Roberta F Capogrosso, and Anna Cozzoli, and Vincenzo Benagiano, and Valeriana Sblendorio, and Simona Ruggieri, and Enrico Crivellato, and Giorgina Specchia, and Domenico Ribatti, and Annamaria De Luca, and Beatrice Nico

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.

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.

UI	MeSH Term	Description	Entries
D007797	Laminin	Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion.	Merosin,Glycoprotein GP-2,Laminin M,Laminin M Chain,Chain, Laminin M,Glycoprotein GP 2,M Chain, Laminin
D008297	Male		Males
D008856	Microscopy, Fluorescence	Microscopy of specimens stained with fluorescent dye (usually fluorescein isothiocyanate) or of naturally fluorescent materials, which emit light when exposed to ultraviolet or blue light. Immunofluorescence microscopy utilizes antibodies that are labeled with fluorescent dye.	Fluorescence Microscopy,Immunofluorescence Microscopy,Microscopy, Immunofluorescence,Fluorescence Microscopies,Immunofluorescence Microscopies,Microscopies, Fluorescence,Microscopies, Immunofluorescence
D011239	Prednisolone	A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states.	Di-Adreson-F,Predate,Predonine,Di Adreson F,DiAdresonF
D001812	Blood-Brain Barrier	Specialized non-fenestrated tightly-joined ENDOTHELIAL CELLS with TIGHT JUNCTIONS that form a transport barrier for certain substances between the cerebral capillaries and the BRAIN tissue.	Brain-Blood Barrier,Hemato-Encephalic Barrier,Barrier, Blood-Brain,Barrier, Brain-Blood,Barrier, Hemato-Encephalic,Barriers, Blood-Brain,Barriers, Brain-Blood,Barriers, Hemato-Encephalic,Blood Brain Barrier,Blood-Brain Barriers,Brain Blood Barrier,Brain-Blood Barriers,Hemato Encephalic Barrier,Hemato-Encephalic Barriers
D003893	Desmin	An intermediate filament protein found predominantly in smooth, skeletal, and cardiac muscle cells. Localized at the Z line. MW 50,000 to 55,000 is species dependent.	Skeletin
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005456	Fluorescent Dyes	Chemicals that emit light after excitation by light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags.	Flourescent Agent,Fluorescent Dye,Fluorescent Probe,Fluorescent Probes,Fluorochrome,Fluorochromes,Fluorogenic Substrates,Fluorescence Agents,Fluorescent Agents,Fluorogenic Substrate,Agents, Fluorescence,Agents, Fluorescent,Dyes, Fluorescent,Probes, Fluorescent,Substrates, Fluorogenic
D005938	Glucocorticoids	A group of CORTICOSTEROIDS that affect carbohydrate metabolism (GLUCONEOGENESIS, liver glycogen deposition, elevation of BLOOD SUGAR), inhibit ADRENOCORTICOTROPIC HORMONE secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system.	Glucocorticoid,Glucocorticoid Effect,Glucorticoid Effects,Effect, Glucocorticoid,Effects, Glucorticoid
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia