American Journal of Translational Research | |
The effect of specific IKKβ inhibitors on the cytosolic expression of IκB-α and the nuclear expression of p65 in dystrophic (MDX) muscle | |
David Bayless1  Elizabeth Dole1  C George Carlson1  Casey Stefanski1  | |
关键词: Duchenne muscular dystrophy; mdx mouse; inflammation; NF-κB signaling; p65; IκB-α; BMS-345541; PHA-408; IκB-α kinase; | |
DOI : | |
学科分类:医学(综合) | |
来源: e-Century Publishing Corporation | |
【 摘 要 】
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.
【 授权许可】
Unknown
【 预 览 】
Files | Size | Format | View |
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RO201912140865942ZK.pdf | 1959KB | download |