The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice

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...

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Autores principales: Sali, Arpana, Many, Gina M., Gordish-Dressman, Heather, van der Meulen, Jack H., Phadke, Aditi, Spurney, Christopher F., Cnaan, Avital, Hoffman, Eric P., Nagaraju, Kanneboyina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699610/
https://www.ncbi.nlm.nih.gov/pubmed/23843959
http://dx.doi.org/10.1371/journal.pone.0066617
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author Sali, Arpana
Many, Gina M.
Gordish-Dressman, Heather
van der Meulen, Jack H.
Phadke, Aditi
Spurney, Christopher F.
Cnaan, Avital
Hoffman, Eric P.
Nagaraju, Kanneboyina
author_facet Sali, Arpana
Many, Gina M.
Gordish-Dressman, Heather
van der Meulen, Jack H.
Phadke, Aditi
Spurney, Christopher F.
Cnaan, Avital
Hoffman, Eric P.
Nagaraju, Kanneboyina
author_sort Sali, Arpana
collection PubMed
description 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
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spelling pubmed-36996102013-07-10 The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice Sali, Arpana Many, Gina M. Gordish-Dressman, Heather van der Meulen, Jack H. Phadke, Aditi Spurney, Christopher F. Cnaan, Avital Hoffman, Eric P. Nagaraju, Kanneboyina PLoS One Research Article 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. Public Library of Science 2013-07-02 /pmc/articles/PMC3699610/ /pubmed/23843959 http://dx.doi.org/10.1371/journal.pone.0066617 Text en © 2013 Sali et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sali, Arpana
Many, Gina M.
Gordish-Dressman, Heather
van der Meulen, Jack H.
Phadke, Aditi
Spurney, Christopher F.
Cnaan, Avital
Hoffman, Eric P.
Nagaraju, Kanneboyina
The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice
title The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice
title_full The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice
title_fullStr The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice
title_full_unstemmed The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice
title_short The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice
title_sort proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699610/
https://www.ncbi.nlm.nih.gov/pubmed/23843959
http://dx.doi.org/10.1371/journal.pone.0066617
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