Résumé :
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Ursodeoxycholic acid (UDCA) is in current clinical use for the treatment of biliary cirrhosis and has been shown to reduce nuclear p65 activation in HeLa cells expressing elevated glucocorticoid receptor (Miura et al., J. Biol. Chem., 276(50), 47371-47378, 2001). Nuclear extracts obtained from mdx diaphragms exposed to 100 or 200 ?M UDCA for 2 hours exhibited a significant 65% reduction in p65 activation in comparison to mdx preparations bathed in HEPES Ringer for the same period. Preparations exposed to 200 ?M UDCA for 4 hours also exhibited significant reductions in nuclear p65 activation to approximately 50% of the levels seen in preparations exposed to HEPES Ringer. To examine the efficacy of UDCA administration, several adult mdx mice were administered a single dose of 5, 10, or 20 mg/kg intraperitoneally and euthanized at 3 and 5 hours after injection (vehicle treated mdx served as controls). UDCA exposure did not reduce nuclear p65 activation at 3 hours after the injection but significantly reduced activation at all 3 doses to approximately 33% of vehicle-treated levels at 5 hours after the injection. Daily treatment of 1 month old mdx mice at 40 mg/kg for a period of 30 days significantly reduced nuclear p65 activation to approximately 60% of vehicle–treated levels. Whole body tension determinations obtained after 30 days of UDCA treatment indicated significant, 24 to 27%, increases in the WBT5 and WBT10 measures (Carlson and Makiejus, Muscle and Nerve, 13:480-484, 1990) corresponding to 31 and 26% recovery in WBT5 and WBT10, respectively. UDCA treatment had no effect on the WBT10/WBT5 ratio or on 4 limb hang time using a wire grid. These experiments suggest that UDCA may be effective in the treatment of Duchenne and related muscular dystrophies. Experiments examining the efficacy of oral administration of UDCA in the mdx mouse are underway. (Supported by AFM, Charley’s Fund, Strategic Research Grant from ATSU)
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