title: 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.affiliation: Department of Physiology, Kirksville College of Osteopathic Medicine, AT Still University Kirksville, MO 63501.
authors.forename: C George
authors.initials: CG
authors.lastname: Carlson
authors.affiliation: Department of Physiology, Kirksville College of Osteopathic Medicine, AT Still University Kirksville, MO 63501.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dole
authors.affiliation: Department of Physiology, Kirksville College of Osteopathic Medicine, AT Still University Kirksville, MO 63501.
authors.forename: Casey
authors.initials: C
authors.lastname: Stefanski
authors.affiliation: Department of Physiology, Kirksville College of Osteopathic Medicine, AT Still University Kirksville, MO 63501.
authors.forename: David
authors.initials: D
authors.lastname: Bayless
keywords: BMS-345541; Duchenne muscular dystrophy; IκB-α; IκB-α kinase; NF-κB signaling; PHA-408; inflammation; mdx mouse; p65