Title

 

Authors

 V. Sblendorio
 
Doctorate School in Biochemical and Pharmacological Sciences
Dept. Pharmaco-Biology, Section of Pharmacology, Faculty of Pharmacy-University of Bari, Italy

 

Abstract

Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disease characterized by the absence of dystrophin [1]. This condition leads to progressive muscle fiber death and impaired regeneration through complex and still unclear pathological mechanisms such as inflammation, fibrosis, altered calcium homeostasis and oxidative stress. Accordingly, drugs with a wide mechanism of action able to target multiple steps of the pathogenetic cascade, such as pentoxifylline (PTX), contrast disease-related indices and enhance muscle performance and regeneration in dystrophic mdx mice [2]. Similar effect can be observed with β-2 agonists, a well-known class of anabolic drugs [3]. We presently focused on anabolic androgens as another pharmacological strategy with possible action on both muscle performance and regeneration, for potential beneficial effect in dystrophic muscles. Controversial data is available on potential usefulness of androgens in DMD [4]. However androgens are known to enhance muscle strength and muscle mass by stimulating protein anabolism. Moreover anabolic steroids may stimulate satellite cell proliferation via either Wnt-β-catenin pathways or IGF-1, that is one major target of androgen action known to exert beneficial effects in dystrophic animals [5, 6]. We presently evaluated the effects of chronic 4-6 weeks treatment with nandrolone (5mg/kg/day s.c.), in comparison with those of α-methyl-prednisolone (PDN),(1mg/kg/day i.p.), the sole drug clinically used for DMD, in the chronically exercised mdx mouse model. In vivo, after 4 weeks of treatment, both drugs led to a significant increase (p<0.01) in maximal forelimb strength. In fact, the fore limb strength values were 0.163±0.009 kg and 0.168±0.008 kg in nandrolone and PDN-treated exercised mdx mice, respectively, versus 0.142±0.006 kg of untreated counterparts. This significant increase was also clearly observable when individual fore-limb strength values were normalized to mouse body weight. However, neither drugs enhanced the resistance of mdx mice to treadmill running. After 4-6 weeks of treatment, the animals have been sacrificed for ex-vivo experiments. By means of spectrophotometry, we evaluated the values of plasma creatine kinase (CK) and reactive oxygen species (ROS), indices of sarcolemma injuryand oxidative stress, respectively, and of lactate dehydrogenase (LDH), an index of metabolic sufferance. Both treatments did not reduce the high levels of CK and ROS, while nandrolone was able to slightly decrease, although not significantly, the values of LDH in treated mdx mice compared to untreated ones. Both treatments induced a partial improvement in the histological profile of the gastrocnemious muscle, with a mild reduction in necrosis and non-muscle area of the treated muscles. Interestingly, in diaphragm, the muscle mostly compromised in mdx mice, a decrease of 64% (p<0.0002) in non-muscle area has been observed in nandrolone-treated muscles compared to untreated ones. This data suggests that nandrolone may exert ameliorative effects on muscle performance and morphology. Further investigation will shed light on the action of nandrolone on markers of fibrosis (TGF-β), and of muscle regeneration (myogenin, PAX7, Wnt/β-Catenin), possibly reinforcing the interest toward this class of drugs for muscular dystrophy (Supported by Charley’s Fund, USA).
 
1) Hoffman EP et al. (2001)-Trends Pharmacol Sci, 22:465-70.
2) Burdi R et al. (2009)-J Appl Physiol, 106 (4):1311-24.
3) Gehrig SM et al. (2010)-Am J Phatol, 176(1):29-33.
4) Fenichel G et al. (2001)-Neurol, 56(8): 1075-9.
5) Layne MD et al. (1999)-Exp Cell Res, 249(1):177-87.
6) De Luca A et al. (2003)-J Pharmacol Exp Ther, 304(1):453-63.