title: Andrographolide attenuates skeletal muscle dystrophy in mdx mice and increases efficiency of cell therapy by reducing fibrosis.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is characterized by the absence of the cytoskeletal protein dystrophin, muscle wasting, increased transforming growth factor type beta (TGF-β) signaling, and fibrosis. At the present time, the only clinically validated treatments for DMD are glucocorticoids. These drugs prolong muscle strength and ambulation of patients for a short term only and have severe adverse effects. Andrographolide, a bicyclic diterpenoid lactone, has traditionally been used for the treatment of colds, fever, laryngitis, and other infections with no or minimal side effects. We determined whether andrographolide treatment of mdx mice, an animal model for DMD, affects muscle damage, physiology, fibrosis, and efficiency of cell therapy.
  
  
  METHODS
  mdx mice were treated with andrographolide for three months and skeletal muscle histology, creatine kinase activity, and permeability of muscle fibers were evaluated. Fibrosis and TGF-β signaling were evaluated by indirect immunofluorescence and Western blot analyses. Muscle strength was determined in isolated skeletal muscles and by a running test. Efficiency of cell therapy was determined by grafting isolated skeletal muscle satellite cells onto the tibialis anterior of mdx mice.
  
  
  RESULTS
  mdx mice treated with andrographolide exhibited less severe muscular dystrophy than untreated dystrophic mice. They performed better in an exercise endurance test and had improved muscle strength in isolated muscles, reduced skeletal muscle impairment, diminished fibrosis and a significant reduction in TGF-β signaling. Moreover, andrographolide treatment of mdx mice improved grafting efficiency upon intramuscular injection of dystrophin-positive satellite cells.
  
  
  CONCLUSIONS
  These results suggest that andrographolide could be used to improve quality of life in individuals with DMD.
authors.affiliation: Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile ; Departamento de Ciencias Químicas y Biológicas, Universidad Bernardo O'Higgins, Santiago, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrera
authors.affiliation: Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Gutiérrez
authors.affiliation: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas & Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
authors.affiliation: Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Morales
authors.affiliation: División de Nefrología, Escuela de Medicina, Universidad Austral, Valdivia, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.affiliation: Departamento de Neurología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Fadic
authors.affiliation: Departamento de Neurología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Casar
authors.affiliation: Instituto de Farmacología, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Hancke
authors.affiliation: Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
keywords: Andrographolide; Cell therapy; DMD; Fibrosis; Skeletal muscle; mdx