G.P.88: Novel inhibitor of hematopoietic prostaglandin D synthase improves the muscle disorder in an experimental model of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a fatal genetic disease. The fibers of muscle in DMD patients easily suffer necrotic change, because of the loss of dystrophin. Thus the patients present with a weakening motor activity. There is still no complete cure for the disease. Recently, we have reported that prostaglandin D2 (PGD2) synthesized by hematopoietic PGD synthase (HPGDS) may play an important role in the pathology of DMD. In this study, we evaluated the beneficial effects of a highly selective HPGDS inhibitor (TAS-205 which is found in our laboratory) in dystrophin-deficient mice. We used dystrophin-deficient mdx mice (C57BL/6 back ground) and the wild-type mice (C57BL/6). Mice were treated with TAS-205 daily by supplied the diet including 0.01% or 0.1% TAS-205 from 5 to 9 weeks of age. Mice of control group and normal group were supplied the same food without drug. At 9 weeks of age, we measured the locomotor activity during night-time, collected the mouse urine of at night-time to determine the urinary concentration of tetranor-PGDM, a metabolite of PGD2, and evaluated the rate of necrotic fibers area in cross sections of the diaphragm muscle. The locomotor activity at the night-time was significantly lower in mdx mice than that in wild-type mice. In histological evaluation, many necrotic fibers were detected in diaphragm muscle of mdx mice but hardly in wild-type mice. The urinary tetranor-PGDM concentration was significantly higher in mdx mice than that in wild-type mice. TAS-205 dose-dependently suppressed the urinary tetranor-PGDM amount in mdx mice. TAS-205 at high dose significantly reduced the necrotic muscle fibers and recovered the locomotor activity in mdx mice. These results indicate that PGD2 synthesized by HPGDS is involved in the progression of muscular necrosis in DMD and a HPGDS inhibitor, such as TAS-205, would be an effective therapy for DMD.