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(American Journal of Pathology. 2005;166:477-489.)
© 2005 American Society for Investigative Pathology

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

Annamaria De Luca*, Beatrice Nico{dagger}, Antonella Liantonio*, Maria Paola Didonna*, Bodvael Fraysse*, Sabata Pierno*, Rosa Burdi*, Domenica Mangieri{dagger}, Jean-François Rolland*, Claudia Camerino{dagger}, Alberta Zallone{dagger}, Paolo Confalonieri{ddagger}, Francesca Andreetta{ddagger}, Elisa Arnoldi{ddagger}, Isabelle Courdier-Fruh§, Josef P. Magyar§, Antonio Frigeri, Michela Pisoni, Maria Svelto and Diana Conte Camerino*

From the Department of Pharmacobiology,* Unit of Pharmacology, and the Departments of Human Anatomy and Histology{dagger} and General and Environmental Physiology, University of Bari, Bari, Italy; the Muscular Pathology Unit,{ddagger} National Neurological Institute Carlo Besta, Milan, Italy; and MyoContract Limited,§ Liestal, Switzerland

Chronic inflammation is a secondary reaction of Duchenne muscular dystrophy and may contribute to disease progression. To examine whether immunosuppressant therapies could benefit dystrophic patients, we analyzed the effects of cyclosporine A (CsA) on a dystrophic mouse model. Mdx mice were treated with 10 mg/kg of CsA for 4 to 8 weeks throughout a period of exercise on treadmill, a protocol that worsens the dystrophic condition. The CsA treatment fully prevented the 60% drop of forelimb strength induced by exercise. A significant amelioration (P < 0.05) was observed in histological profile of CsA-treated gastrocnemius muscle with reductions of nonmuscle area (20%), centronucleated fibers (12%), and degenerating area (50%) compared to untreated exercised mdx mice. Consequently, the percentage of normal fibers increased from 26 to 35% in CsA-treated mice. Decreases in creatine kinase and markers of fibrosis were also observed. By electrophysiological recordings ex vivo, we found that CsA counteracted the decrease in chloride conductance (gCl), a functional index of degeneration in diaphragm and extensor digitorum longus muscle fibers. However, electrophysiology and fura-2 calcium imaging did not show any amelioration of calcium homeostasis in extensor digitorum longus muscle fibers. No significant effect was observed on utrophin levels in diaphragm muscle. Our data show that the CsA treatment significantly normalized many functional, histological, and biochemical endpoints by acting on events that are independent or downstream of calcium homeostasis. The beneficial effect of CsA may involve different targets, reinforcing the usefulness of immunosuppressant drugs in muscular dystrophy.




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