Preclinical Trials of NFkappaB Inhibition in the Treatment of Muscular Dystrophy

摘要

ABSTRACT Recent evidence obtained in this laboratory indicates that treatments which reduce the nuclear activation of the transcription factor nuclear factor-kappaB (NF?B) have distinct beneficial effects in substantially reducing the loss of striated muscle fibers and restoring the resting membrane potential in severely dystrophic (mdx) muscle fibers [2]. These results indicate a clear need for investigating the potential clinical utility of NF?B inhibitors in treating Duchenne and Becker muscular dystrophies. The purpose of these proposed studies is to determine the clinical utility of sulfasalazine which inhibits the NF?B pathway in dystrophic muscle. Sulfasalazine is of particular interest because it is currently used on a chronic basis to treat inflammatory disorders in both adults and children. Undergraduate, graduate, and D.O. students (A.T. Still University, Truman State University) will be involved in assessing the effects of sulfasalazine treatment on tension development in two isolated mdx muscles (gastrocnemius, costal diaphragm) and on whole body strength in intact mdx mice. This study is done in parallel with translational investigations that include assessments of cytosolic and nuclear levels of NF?B in chronically treated mdx muscle, the expression of inflammatory cytokines in plasma and muscle extracts, resting membrane potential, plasma creatine kinase levels, skeletal muscle fibrosis, and histological determinations of the total number of fibers, the proportion of striated vs necrotic fibers, percent centronucleation, and the distribution of fiber diameter and cross sectional areas in dystrophic mdx muscle. The proposed studies will test the specific hypothesis that sulfasalazine treatment improves muscle function in the mdx mouse and will provide essential pre-clinical information that can be used in clinical trials for patients with Duchenne and Becker muscular dystrophies. PROJECT NARRATIVE These studies will examine the potential therapeutic efficacy of sulfasalazine which is a member of a class of drugs (NF?B inhibitors) that have recently been shown to have beneficial effects in the mdx mouse, a model for Duchenne muscular dystrophy. Sulfasalazine is currently used to treat inflammatory conditions in both children and adults, and the results of the proposed investigations will provide critical information for establishing clinical trials to test the efficacy of sulfasalazine in treating patients with Duchenne and Becker muscular dystrophy.