A robust in vitro screening assay to identify NF-κB inhibitors for inflammatory muscle diseases

Baudy, Andreas R.; Saxena, Nandita; Gordish, Heather; Hoffman, Eric P.; Nagaraju, Kanneboyina

doi:10.1016/j.intimp.2009.07.001

Cited by 30 publications

(30 citation statements)

References 23 publications

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“…Celastrol has been shown to suppress IκB phosphorylation and NF-κB activation by inhibiting TAK1 activation (17). We have previously developed a muscle-based NF-κB inhibitor screening assay and shown that celastrol is one of the powerful inhibitors of NF-κB under this system (18). Based on this data, inhibition of NF-κB anti-inflammatory agents such as celastrol to suppress immune activation in dysferlin-deficient muscle could ameliorate the disease pathology.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice

Dillingham

Klimek

Gernapudi

et al. 2015

Journal of the Neurological Sciences

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The dysferlin-deficient A/J mouse strain represents a homologous model for limb-girdle muscular dystrophy 2B. We evaluated the disease phenotype in 10 month old A/J mice compared to two dysferlin-sufficient, C57BL/6 and A/JOlaHsd, mouse lines to determine which functional end-points are sufficiently sensitive to define the disease phenotype for use in preclinical studies in the A/J strain. A/J mice had significantly lower open field behavioral activity (horizontal activity, total distance, movement time and vertical activity) when compared to C57BL/6 and A/JoIaHsd mice. Both A/J and A/JOIaHsd mice showed decreases in latency to fall with rotarod compared to C57BL/6. No changes were detected in grip strength, force measurements or motor coordination between these three groups. Furthermore, we have found that A/J muscle shows significantly increased levels of the pro-inflammatory cytokine TNF-α when compared to C57BL/6 mice, indicating an activation of NF-κB signaling as part of the inflammatory response in dysferlin-deficient muscle. Therefore, we assessed the effect of celastrol (a potent NF-κB inhibitor) on the disease phenotype in female A/J mice. Celastrol treatment for four months significantly reduced the inflammation in A/J muscle; however, it had no beneficial effect in improving muscle function, as assessed by grip strength, open field activity, and in vitro force contraction. In fact, celastrol treated mice showed a decrease in body mass, hindlimb grip strength and maximal EDL force. These findings suggest that inhibition of inflammation alone may not be sufficient to improve the muscle disease phenotype in dysferlin-deficient mice and may require combination therapies that target membrane stability to achieve a functional improvement in skeletal muscle.

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Section: Introductionmentioning

confidence: 99%

Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice

Dillingham

Klimek

Gernapudi

et al. 2015

Journal of the Neurological Sciences

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“…The in vitro drug screening assay for NF-B inhibition in C 2 C 12 cells was done as described previously (Baudy et al, 2009). To measure the ablation of NF-B effects by the addition of a GR antagonist, reporter cells were pretreated for 1 h with the drug at a constant concentration and 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[1-propynyl]estra-4,9-dien-3-one (RU-486) at increasing concentrations (1 nM to 10 M).…”

Section: Nf-b Inhibitionmentioning

confidence: 99%

“…Force measurements were conducted on the extensor digitorum longus muscle of the right hindlimb of the mdx mouse as described previously (Spurney et al, 2011). Dissociative ⌬-9,11 Steroids and studied drug effects on both undifferentiated myoblasts and multinucleated myotubes (Baudy et al, 2009). We synthesized anecortave, and the 21-hydroxy desacetate form, VBP1 ( Fig.…”

Section: Baudy Et Almentioning

confidence: 99%

Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

Baudy

Reeves

Damsker

et al. 2012

J Pharmacol Exp Ther

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Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoidsdrugs able to retain or improve efficacy associated with transrepression [nuclear factor-B (NF-B) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a ⌬-9,11 modification as a dissociative steroid. The ⌬-9,11 analog showed potent inhibition of tumor necrosis factor-␣-induced NF-B signaling in cell reporter assays, and this transrepression activity was blocked by 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The ⌬-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GRluciferase constructs as well as mRNA profiles of treated cells. The ⌬-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the ⌬-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a ⌬-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, ⌬-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.

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“…This protein-protein complex inhibits the activity of a large number of pro-inflammatory transcription factors, including NFjB, without binding to DNA [7]. Decreased transcription of NFjB results in decreased production of several pathogenic cytokines and chemokines [8][9][10]. Another mechanism of GC activity, known as transactivation, occurs when the GR-steroid complex forms a homodimer in the cytosol, and crosses the nuclear membrane.…”

Section: Introductionmentioning

confidence: 99%

VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

et al. 2016

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A robust in vitro screening assay to identify NF-κB inhibitors for inflammatory muscle diseases

Cited by 30 publications

References 23 publications

Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice

Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice

Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

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