Inhibition of Allergic Dermal Inflammation by the Novel Imidazopyridazine Derivative TAK-427 in a Guinea Pig Experimental Model of Eczema

Fukuda, Shoko; Midoro, Katsuo; Kamei, Takayuki; Gyoten, Michiyo; Kawano, Yukio; Ashida, Yuzuru; Nagaya, Hideaki

doi:10.1124/jpet.102.040105

Cited by 19 publications

(9 citation statements)

References 32 publications

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“…Keratinocytes at the site of CD overexpress numerous cytokines and chemokines, such as TNF-α, IFN-γ, MCP-1 and IL-10 (17-19). It has been previously reported that IFN-γ is important in the development of skin hypertrophy, and TNF-α and MCP-1 function as stimulants of immune cell recruitment around blood vessels (17)(18)(19). In the present study, the topical application of MEKS inhibited the histopathological features of CD via suppression of TNF-α, IFN-γ and MCP-1 expression.…”

supporting

confidence: 59%

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Ryu

Han

et al. 2015

Molecular Medicine Reports

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Abstract. The mature fruit of Kochia scoparia (L.) Schrad. is widely administered in China and Korea as a medicinal herb for treatment of skin diseases, diabetes mellitus and rheumatoid arthritis. The present study investigated the effects of methanol extracts of K. scoparia dried fruit (MEKS) on ear swelling, histopathological changes (such as epidermal acanthosis, spongiosis and immune cell infiltration) and cytokine production in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis mice. Topical application of MEKS inhibited DNFB-induced ear thickness and weight increases, as well as DNFB-induced epidermal acanthosis, spongiosis and immune cell infiltration. In addition, treatment with MEKS significantly decreased the levels of tumor necrosis factor-α, interferon-γ and monocyte chemotactic protein-1 in inflamed tissues. These data indicate that the mature fruit of K. scoparia has the potential to be administered for the treatment of inflammatory skin diseases and that the anti-inflammatory action of K. scoparia is involved in the inhibition of type 1 T helper cell skewing reactions.

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supporting

confidence: 59%

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Ryu

Han

et al. 2015

Molecular Medicine Reports

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“…NOD2/TLR2 ligand treatment alone did not induce effects in the absence of MC903 (Figure 1a-e and g and h), suggesting that the deteriorating effects of the NOD2/TLR2 ligands might only occur in pre-established skin lesions wherein the epidermal barrier function is disturbed. Previous publications have shown that eosinophil infiltration might only be observed in the dermal layer of AD skin lesions; 24,29 however, here we found that topical S. aureus-associated NOD2/TLR2 ligands led to further epidermal infiltration of eosinophils in our mouse model of AD-like skin inflammation induced by MC903 (Figure 1f). …”

Section: Topical Application Of Nod2/tlr2 Ligands Induced Exacerbatiocontrasting

confidence: 42%

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

et al. 2015

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The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil-fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD. Cellular & Molecular Immunology

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“…-yl]-2-methylpropionic acid dihydrate (TAK-427) was developed as a therapeutic agent for atopic dermatitis [6]. In an in vitro pharmacokinetic study, the transport of TAK-427 across Caco-2 cells was in a predominantly secretory direction suggesting that TAK-427 could be a substrate for P-gp.…”

Section: -[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazomentioning

confidence: 99%

Marked impact of P‐glycoprotein on the absorption of TAK‐427 in rats

Takeuchi

Nonaka

Yoshitomi

et al. 2008

Biopharm & Drug Disp

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The role of P-glycoprotein (P-gp, ABCB1) on the absorption process was investigated by drug-drug interaction studies of TAK-427 with P-gp inhibitors (erythromycin, ketoconazole or quinidine) in rats and by transport studies using rat multidrug resistance (MDR1) stably expressing cells and rat small intestine mounted in a Ussing-type chamber. TAK-427 showed high efflux activity with low permeability in rat MDR1a and MDR1b stably expressing cells and was revealed to be a typical substrate for P-gps. Although TAK-427 was mainly absorbed from the small intestine in rats, a large part of the dosed compound remained in the gastrointestinal tract. Orally co-administered P-gp inhibitors (50 mg/kg) increased the AUC of TAK-427 after a 5 mg/kg oral dose 5.4- to 18.3-fold, whereas orally administered P-gp inhibitors had a minor effect on the increase in the AUC of TAK-427 (1.3- to 2.2-fold) after a 0.5 mg/kg intravenous dose. Thus, the bioavailability of TAK-427 after oral administration in rats (7.3%) markedly increased when co-administered with P-gp inhibitors (28.6-57.6%). Moreover, the transport of TAK-427 was predominantly secretory throughout the rat small intestine and was inhibited by P-gp inhibitors. In conclusion, P-gp can markedly reduce the absorption of a typical P-gp substrate by its efflux activity throughout the absorption site.

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Inhibition of Allergic Dermal Inflammation by the Novel Imidazopyridazine Derivative TAK-427 in a Guinea Pig Experimental Model of Eczema

Cited by 19 publications

References 32 publications

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

Marked impact of P‐glycoprotein on the absorption of TAK‐427 in rats

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