VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects

Autor: Christopher R. Heier, Edward M. Connor, Kathleen Tatem, Kanneboyina Nagaraju, Sarah Jordan, Luana Scheffer, Qing Yu, Tony Huynh, Michael E. Calhoun, Jack H. Van der Meulen, Olga Rodriguez, John M. McCall, Heather Gordish-Dressman, Erica K.M. Reeves, Sherry Dadgar, Eric P. Hoffman, Chris Albanese, Jesse M. Damsker, Arpana Sali, Brittany K. Miller, James L Quinn, Aditi Phadke, Blythe C. Dillingham, Jyoti K. Jaiswal
Rok vydání: 2013
Předmět:
Transcription
Genetic
muscle
T-Lymphocytes
Duchenne muscular dystrophy
Anti-Inflammatory Agents
Pharmacology
Muscular Dystrophies
Myoblasts
Mice
0302 clinical medicine
Glucocorticoid receptor
Protein Interaction Maps
Muscular dystrophy
Pregnadienediols
Research Articles
anti-inflammatory
0303 health sciences
biology
NF-kappa B
3. Good health
Phenotype
medicine.anatomical_structure
dystrophy
Prednisolone
Molecular Medicine
medicine.symptom
Dystrophin
mdx
Immunosuppressive Agents
Signal Transduction
medicine.drug
Inflammation
Cell Line
Necrosis
03 medical and health sciences
Receptors
Glucocorticoid
medicine
Animals
030304 developmental biology
Lasers
Cell Membrane
Dystrophy
Skeletal muscle
medicine.disease
Immunology
Mice
Inbred mdx
biology.protein
membrane injury
030217 neurology & neurosurgery
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
Popis: Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.
Databáze: OpenAIRE
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