G.P.91 : Diapocynin, a putative NADPH oxidase inhibitor, ameliorates the phenotype of a mouse model of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked muscular disease that causes premature death and for which no cure exists. We have shown previously that in vitro treatment of dystrophic myotubes and excised muscles with diapocynin, a dimer of the classically used NADPH oxidase inhibitor apocynin, ameliorated several molecular events involved in DMD pathogenesis, of which ROS production, phospholipase A2 activity, Ca 2+ influx and sarcolemmal integrity. Here, we report on the in vivo effects of diapocynin and apocynin in mdx 5Cv dystrophic mice, a model of DMD. Apocynin (50mg/kg/day) and diapocynin (10 and 100mg/kg/day) were given orally to mdx 5Cv mouse pups, first via the lactating mothers from post-natal day 14 to 28 and subsequently directly to the weaned pups till post-natal day 35±1 or 60±3. Diapocynin but not apocynin enhanced spontaneous locomotor activity, rescued voluntary wheel running capabilities, and ameliorated diaphragm structure of dystrophic mice. Diapocynin and apocynin were equally potent at increasing the resistance to fatigue of triceps surae muscles exposed to repeated isometric contractions in situ and at preserving sarcolemmal integrity as evidenced by Evans blue dye uptake. Furthermore, microarray analyses showed a tendency of the treatments to correct gene expression in dystrophic mice towards wild type controls. Although apocynin and diapocynin had beneficial effects in dystrophic mice, diapocynin was superior in improving locomotion.