title: A multidisciplinary evaluation of the effectiveness of cyclosporine a in dystrophic mdx mice.
abstract: 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.
authors.affiliation: Sezione di Farmacologia, Dipartimento Farmacobiologico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, Campus, 70125 Bari, Italy. adeluca@farmbiol.uniba.it
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Didonna
authors.forename: Bodvael
authors.initials: B
authors.lastname: Fraysse
authors.forename: Sabata
authors.initials: S
authors.lastname: Pierno
authors.forename: Rosa
authors.initials: R
authors.lastname: Burdi
authors.forename: Domenica
authors.initials: D
authors.lastname: Mangieri
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rolland
authors.forename: Claudia
authors.initials: C
authors.lastname: Camerino
authors.forename: Alberta
authors.initials: A
authors.lastname: Zallone
authors.forename: Paolo
authors.initials: P
authors.lastname: Confalonieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Andreetta
authors.forename: Elisa
authors.initials: E
authors.lastname: Arnoldi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Courdier-Fruh
authors.forename: Josef P
authors.initials: JP
authors.lastname: Magyar
authors.forename: Antonio
authors.initials: A
authors.lastname: Frigeri
authors.forename: Michela
authors.initials: M
authors.lastname: Pisoni
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004396:Coloring Agents / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D004594:Electrophysiology; D005355:Fibrosis; D016257:Fura-2 / Q000494:pharmacology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007477:Ions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects; D009132:Muscles / Q000187:drug effects; D009136:Muscular Dystrophies / Q000188:drug therapy*; D010805:Physical Conditioning, Animal; D013053:Spectrophotometry; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: D002712:Chlorides; D004396:Coloring Agents; D007166:Immunosuppressive Agents; D007477:Ions; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D003402:Creatine Kinase; D002118:Calcium; D016257:Fura-2