C. Weller and J. Zschüntzsch contributed equally to this work.
Motor performance of young dystrophic mdx mice treated with long-circulating prednisolone liposomes
Article first published online: 18 JAN 2012
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Neuroscience Research
Volume 90, Issue 5, pages 1067–1077, May 2012
How to Cite
Weller, C., Zschüntzsch, J., Makosch, G., Metselaar, J. M., Klinker, F., Klinge, L., Liebetanz, D. and Schmidt, J. (2012), Motor performance of young dystrophic mdx mice treated with long-circulating prednisolone liposomes. J. Neurosci. Res., 90: 1067–1077. doi: 10.1002/jnr.22825
- Issue published online: 7 MAR 2012
- Article first published online: 18 JAN 2012
- Manuscript Accepted: 21 OCT 2011
- Manuscript Revised: 19 OCT 2011
- Manuscript Received: 8 MAY 2011
- Duchenne muscular dystrophy;
- mdx mouse;
- liposomal prednisolone;
- voluntary wheel running
For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3–6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-β and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases. © 2012 Wiley Periodicals, Inc.