Abstract
The efficacy of two highly specific IκB-α kinase β (IKK-β) inhibitors in reducing the enhanced basal activation of the NF-κB pathway in dystrophic muscle was assessed by determining the effects of these inhibitors in increasing the expression of cytosolic IκB-α and reducing the enhanced expression of nuclear p65 in adult mdx costal diaphragm preparations. In vivo and in vitro treatment with BMS-345541 was ineffective at altering these variables when administered at concentrations that were highly effective in models of acute inflammation. PHA-408 increased cytosolic IκB-α and reduced nuclear p65 at a concentration in vitro (20 μM) that was 500 fold higher than the IC50 for inhibiting purified activity. Long term daily oral administration of PHA-408 increased cytosolic IκB-α but did not influence nuclear p65. Long term intraperitoneal administration of PHA-408 reduced nuclear p65 by approximately 50%. In comparison to their potent effects in models of acute inflammation, these results indicate a reduced efficacy of the specific IKKβ inhibitors in ameliorating the enhanced basal activation of the NF-κB pathway in dystrophic muscle, and suggest that the therapeutic potential of IKK-β inhibitors in treating muscular dystrophy would be enhanced by simultaneous treatment with agents which more directly interfere with NF-κB transactivation.