Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model

Takano, Norikazu; Sakurai, Takanobu; Ohashi, Yuichi; Kurachi, Michio

doi:10.1111/j.1365-2133.2006.07636.x

Cited by 53 publications

(39 citation statements)

References 46 publications

(56 reference statements)

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“…52) Similarly, application of the TrkA antagonists AG879 and K252a to the nape of atopic nc/nga mice significantly improved established dermatitis and scratching behavior and reduced the numbers of nerve fibers in the epidermis, suggesting the importance of nGf in the pathogenesis of atopic dermatitis-like skin lesions. 53) thus, nGf and its receptors may be among the antipruritic targets in pruritic skin diseases such as atopic dermatitis.…”

Section: Anti-ngf Antibody and Ngf Receptor Antagonistsmentioning

confidence: 99%

An Update on Peripheral Mechanisms and Treatments of Itch

Tominaga

Takamori

2013

Biological & Pharmaceutical Bulletin

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Histamine H 1 -receptor blockers are used to treat all types of itch resulting from serious skin diseases such as atopic dermatitis, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life. The development of effective treatments requires a full understanding of the fundamental mechanisms of itch. Recent studies have indicated that the pathogenic mechanisms of itch also involve agonists other than histamine, including proteases, neuropeptides, cytokines, and opioids, as well as their cognate receptors. Release of these pruritogenic mediators and modulators into the periphery may directly activate itch-mediating C-fibers via specific receptors on the nerve terminals. Histological observations have shown increased epidermal nerve densities in patients with atopic dermatitis, suggesting that the higher density is at least partly responsible for itch sensitization. This

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Section: Anti-ngf Antibody and Ngf Receptor Antagonistsmentioning

confidence: 99%

An Update on Peripheral Mechanisms and Treatments of Itch

Tominaga

Takamori

2013

Biological & Pharmaceutical Bulletin

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“…This is likely due to the increased levels of NGF and PGP9.5 in mite-infested Cftr DF508/DF508 mice because treatment of Cftr DF508/DF508 mice with K252a, a high-affinity NGF receptor inhibitor that is also shown to dampen PGP9.5 expression via NGF suppression, 8 significantly inhibited the scratching behavior in mite-infested Cftr DF508/DF508 mice. Although we cannot exclude the possibility of occurrence of increased levels of NGF and PGP9.5 in mite-free Cftr DF508/DF508 mice, our results propose that CFTR dysfunction may correlate with neurite outgrowth in/into epidermis accompanied with NGF hyperproduction in mice kept together with mite-infested NC/Nga mice.…”

Section: Discussionmentioning

confidence: 99%

“…6 It has been demonstrated that nerve growth factor (NGF) plays roles in the pathogenesis of itch and itch-induced skin lesions using skin-lesioned NC/Nga mice, an animal model for human AD, and that inhibiting the physiological effects and production of NGF prevents these symptoms. 7,8 Furthermore, AD patients with itch showed significant gains in NGF plasma levels compared to controls, and a correlation was noted between plasma NGF and severity of symptoms. 9 Thus, NGF plays a role in the regulation of susceptibility to itch reaction and skin lesions.…”

mentioning

confidence: 94%

CFTR-deficiency renders mice highly susceptible to cutaneous symptoms during mite infestation

Hashimoto

Shuto

Mizunoe

et al. 2011

Laboratory Investigation

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Pruritus, also known as itch, is a sensation that causes a desire to scratch. Prolonged scratching exacerbates skin lesions in several skin diseases such as atopic dermatitis. Here, we identify the cystic fibrosis transmembrane conductance regulator (CFTR/Cftr), an integral membrane protein that mediates transepithelial chloride transport, as a determinant factor in mice for the susceptibility to several cutaneous symptoms during mite infestation. Mice that endogenously express dysfunctional Cftr (Cftr DF508/DF508 ) show significant increase of scratching behavior and skin fibrosis after mite exposure. These phenotypes were due to the increased expression of nerve growth factor (NGF) that augments the sensitization of peripheral nerve fibers. Moreover, protein gene product 9.5 (PGP9.5)-positive neurites were abundant in the epidermis of mite-infested Cftr DF508/DF508 mice. Furthermore, mite-infested Cftr þ / þ mice orally administered with a chloride channel inhibitor glibenclamide had higher scratching count and increased level of NGF than vehicle-treated mice. Consistently, mite extract-exposed primary and transformed human keratinocytes, treated with CFTR inhibitor, had significantly higher level of NGF mRNA compared with vehicle-treated, mite extract-exposed cells. These results reveal that CFTR in keratinocytes plays a critical role for the regulation of peripheral nerve function and pruritus sensation, and suggest that Cftr DF508/DF508 mice may serve as a novel mouse model that represents NGF-dependent generation of pruritus.

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“…In fact, high-affinity NGF-receptor inhibitors, AG879 and K252a, are effective in improving the established dermatitis (50) and scratching behavior in the NC/Nga atopic dermatitis model mouse (51), and anti-NGF antibody is also effective in inhibiting epidermal innervation and scratching in NC/Nga mouse (52). However, complete interception of NGF signaling may cause some side effects because autocrined NGF is thought to be involved in keratinocyte proliferation and important for normal elongation of neuronal fibers.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Cytokine Tumor Necrosis Factor-α Enhances Nerve Growth Factor Production in Human Keratinocytes, HaCaT Cells

Takaoka¹,

Shirai²,

Saito³

2009

J Pharmacol Sci

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Abstract. The skin lesions of inflammatory skin diseases (e.g., atopic dermatitis or psoriasis) accompany infiltration of inflammatory cells like macrophages, where abnormal sensory innervations and elevation of nerve growth factor (NGF) level are observed. It is thought that increased NGF mediates the abnormal innervations and this may cause the hypersensitivity of the skin. However, the mechanism of this increased NGF production in the skin is still unknown. Here, we show that tumor necrosis factor (TNF)-α, but not interferon-γ or interleukin-6, enhanced the NGF production in human keratinocytes. The enhanced NGF production was abolished by both Raf-1 kinase and MEK inhibitors, whereas specific inhibitors of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase did not. The extracellular signal-regulated kinase (ERK) phosphorylation and expression of NGF mRNA were accelerated by TNF-α treatment. Furthermore, serum was necessary for the NGF production and epidermal growth factor could substitute for serum in the effect on NGF secretion. These results indicate that TNF-α enhances NGF production via the Raf-1 / MEK / ERK pathway in human keratinocytes, suggesting that regulating TNF-α is a therapeutic target to control NGF production and subsequent sensory innervations.

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Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model

Abstract: We suggest that NGF plays an important role in the pathogenesis of atopic dermatitis-like skin lesions via the high-affinity NGF receptor. These findings provide a new potential therapeutic approach for the amelioration of symptoms of atopic dermatitis.

Cited by 53 publications

References 46 publications

An Update on Peripheral Mechanisms and Treatments of Itch

An Update on Peripheral Mechanisms and Treatments of Itch

CFTR-deficiency renders mice highly susceptible to cutaneous symptoms during mite infestation

Inflammatory Cytokine Tumor Necrosis Factor-α Enhances Nerve Growth Factor Production in Human Keratinocytes, HaCaT Cells

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