A multidisciplinary evaluation of the effectiveness of cyclosporine a in dystrophic mdx mice.
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.
De Luca
Annamaria
A
Sezione di Farmacologia, Dipartimento Farmacobiologico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, Campus, 70125 Bari, Italy. adeluca@farmbiol.uniba.it
Nico
Beatrice
B
Liantonio
Antonella
A
Didonna
Maria Paola
MP
Fraysse
Bodvael
B
Pierno
Sabata
S
Burdi
Rosa
R
Mangieri
Domenica
D
Rolland
Jean-François
JF
Camerino
Claudia
C
Zallone
Alberta
A
Confalonieri
Paolo
P
Andreetta
Francesca
F
Arnoldi
Elisa
E
Courdier-Fruh
Isabelle
I
Magyar
Josef P
JP
Frigeri
Antonio
A
Pisoni
Michela
M
Svelto
Maria
M
Conte Camerino
Diana
D
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
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