The effect of specific IKKβ inhibitors on the cytosolic expression of IκB-α and the nuclear expression of p65 in dystrophic (MDX) muscle.

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.

• Authors: C George Carlson, Elizabeth Dole, Casey Stefanski, David Bayless
• Journal: American journal of translational research (Am J Transl Res) Vol. 7 Issue 4 Pg. 670-82 ( 2015) ISSN: 1943-8141 [Print] United States
• PMID: 26064436 (Publication Type: Journal Article)