title: The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice.
abstract: BACKGROUND
  In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology.
  
  
  RESULTS
  We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions.
  
  
  CONCLUSIONS
  Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and prednisolone combined treatment regimens in dystrophic pathology.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Gina M
authors.initials: GM
authors.lastname: Many
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Jack H
authors.initials: JH
authors.lastname: van der Meulen
authors.forename: Aditi
authors.initials: A
authors.lastname: Phadke
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: Avital
authors.initials: A
authors.lastname: Cnaan
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology; D064747:Lansoprazole / Q000494:pharmacology*; D051379:Mice; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
chemical_list: D016189:Dystrophin; D005938:Glucocorticoids; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D011239:Prednisolone