Multiple pathological events in exercised dystrophic mdx mice are targeted by pentoxifylline: outcome of a large array of in vivo and ex vivo tests.
The phosphodiesterases inhibitor pentoxifylline gained attention for Duchenne muscular dystrophy therapy for its claimed anti-inflammatory, antioxidant, and antifibrotic action. A recent finding also showed that pentoxifylline counteracts the abnormal overactivity of a voltage-independent calcium channel in myofibers of dystrophic mdx mice. The possible link between workload, altered calcium homeostasis, and oxidative stress pushed toward a more detailed investigation. Thus a 4- to 8-wk treatment with pentoxifylline (50 mg x kg(-1) x day(-1) ip) was performed in mdx mice, undergoing or not a chronic exercise on treadmill. In vivo, the treatment partially increased forelimb strength and enhanced resistance to treadmill running in exercised animals. Ex vivo, pentoxifylline restored the mechanical threshold, an electrophysiological index of calcium homeostasis, and reduced resting cytosolic calcium in extensor digitorum longus muscle fibers. Mn quenching and patch-clamp technique confirmed that this effect was paralleled by a drug-induced reduction of membrane permeability to calcium. The treatment also significantly enhanced isometric tetanic tension in mdx diaphragm. The plasma levels of creatine kinase and reactive oxygen species were both significantly reduced in treated-exercised animals. Dihydroethidium staining, used as an indicator of reactive oxygen species production, showed that pentoxifylline significantly reduced the exercise-induced increase in fluorescence in the mdx tibialis anterior muscle. A significant decrease in connective tissue area and profibrotic cytokine transforming growth factor-beta(1) was solely found in tibialis anterior muscle. In both diaphragm and gastrocnemius muscle, a significant increase in neural cell adhesion molecule-positive area was instead observed. This data supports the interest toward pentoxifylline and allows insight in the level of cross talk between pathogenetic events in workloaded dystrophic muscle.
Burdi
Rosa
R
Unit of Pharmacology, Department of Pharmaco-biology, Faculty of Pharmacy, University of Bari, Bari, Italy.
Rolland
Jean-François
JF
Fraysse
Bodvael
B
Litvinova
Karina
K
Cozzoli
Anna
A
Giannuzzi
Viviana
V
Liantonio
Antonella
A
Camerino
Giulia Maria
GM
Sblendorio
Valeriana
V
Capogrosso
Roberta Francesca
RF
Palmieri
Beniamino
B
Andreetta
Francesca
F
Confalonieri
Paolo
P
De Benedictis
Leonarda
L
Montagnani
Monica
M
De Luca
Annamaria
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004594:Electrophysiology; D005456:Fluorescent Dyes; D016257:Fura-2; D007150:Immunohistochemistry; D007537:Isometric Contraction / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008839:Microelectrodes; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D018408:Patch-Clamp Techniques; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010805:Physical Conditioning, Animal / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D005456:Fluorescent Dyes; D010726:Phosphodiesterase Inhibitors; D017382:Reactive Oxygen Species; D003402:Creatine Kinase; D010431:Pentoxifylline; D002118:Calcium; D016257:Fura-2