Evaluation of potential synergistic action of a combined treatment with alpha-methyl-prednisolone and taurine on the mdx mouse model of Duchenne muscular dystrophy.
OBJECTIVE
Glucocorticoids are the sole drugs clinically used in Duchenne muscular dystrophy, in spite of the relevant side effects. Combination of glucocorticoids with synergistic drugs may be one strategy to lower doses and control side effects, meanwhile providing wider control of the complex pathology. This study is a preclinical evaluation of the effect of a combined treatment of α-methyl-prednisolone (PDN) with taurine, a safe aminoacid with positive effects on some pathology-related events.


METHODS
PDN (1 mg/kg/day i.p.) and taurine (1 g/kg/day orally) were administered either alone or in combination, for 4-8 weeks to male dystrophic mdx mice chronically exercised on a treadmill. Effects were assessed in vivo and ex vivo with a variety of methodological approaches.


RESULTS
In vivo, each treatment significantly increased fore limb strength, a marked synergistic effect being observed with the combination PDN + taurine. Ex vivo, PDN + taurine completely restored the mechanical threshold, an electrophysiological index of calcium homeostasis, of extensor digitorum longus myofibres and the benefit was greater than for PDN alone. In parallel, the overactivity of voltage-independent cation channels in dystrophic myofibres was reduced. No effects were observed on plasma levels of creatine kinase, while lactate dehydrogenase was decreased by taurine and, to a minor extent, by PDN + taurine. A similar histology profile was observed in PDN and PDN + taurine-treated muscles. PDN + taurine significantly increased taurine level in fast-twitch muscle and brain, by high-pressure liquid chromatography analysis.


CONCLUSIONS
The combination PDN + taurine has additive actions on in vivo and ex vivo functional end points, with less evident advantages on histopathology and biochemical markers of the disease.
Cozzoli
A
A
Unit of Pharmacology, Department of Pharmaco-biology, Faculty of Pharmacy Department of Human Anatomy and Histology, Faculty of Medicine, University of Bari Metabolic Disease Unit, Paediatric Hospital Giovanni XXIII, Bari, Italy.
Rolland
J-F
JF
Capogrosso
R F
RF
Sblendorio
V T
VT
Longo
V
V
Simonetti
S
S
Nico
B
B
De Luca
A
A
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D013654:Taurine / Q000008:administration & dosage*
D005938:Glucocorticoids; D013654:Taurine; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D008775:Methylprednisolone