title: Diapocynin, a dimer of the NADPH oxidase inhibitor apocynin, reduces ROS production and prevents force loss in eccentrically contracting dystrophic muscle.
abstract: Elevation of intracellular Ca2+, excessive ROS production and increased phospholipase A2 activity contribute to the pathology in dystrophin-deficient muscle. Moreover, Ca2+, ROS and phospholipase A2, in particular iPLA2, are thought to potentiate each other in positive feedback loops. NADPH oxidases (NOX) have been considered as a major source of ROS in muscle and have been reported to be overexpressed in muscles of mdx mice. We report here on our investigations regarding the effect of diapocynin, a dimer of the commonly used NOX inhibitor apocynin, on the activity of iPLA2, Ca2+ handling and ROS generation in dystrophic myotubes. We also examined the effects of diapocynin on force production and recovery ability of isolated EDL muscles exposed to eccentric contractions in vitro, a damaging procedure to which dystrophic muscle is extremely sensitive. In dystrophic myotubes, diapocynin inhibited ROS production, abolished iPLA2 activity and reduced Ca2+ influx through stretch-activated and store-operated channels, two major pathways responsible for excessive Ca2+ entry in dystrophic muscle. Diapocynin also prevented force loss induced by eccentric contractions of mdx muscle close to the value of wild-type muscle and reduced membrane damage as seen by Procion orange dye uptake. These findings support the central role played by NOX-ROS in the pathogenic cascade leading to muscular dystrophy and suggest diapocynin as an effective NOX inhibitor that might be helpful for future therapeutic approaches.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Ismail
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
authors.forename: Urs T
authors.initials: UT
authors.lastname: Ruegg
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Dorchies
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D020013:Calcium Signaling / Q000187:drug effects; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2 / Q000096:biosynthesis / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D001713:Biphenyl Compounds; D016189:Dystrophin; D017382:Reactive Oxygen Species; C527766:diapocynin; D019255:NADPH Oxidases; D054467:Phospholipases A2