gyemin noh

Topical Application of a PDE4 InhibitorAmeliorates Atopic Dermatitis throughInhibition of Basophil IL-4 Production

Abstract

Phosphodiesterase 4 inhibitors have been approved for the treatment of atopic dermatitis. However, the
cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. In this
study, we addressed this unsolved issue by analyzing the action of difamilast, a novel phosphodiesterase 4
inhibitor, on an oxazolone-induced skin allergic inflammation commonly used as a mouse model of atopic
dermatitis. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4
expression even when the treatment commenced 4 days after the initiation of oxazolone challenge, showing
its therapeutic effect on atopic dermatitis. IL-4edeficient mice displayed milder skin inflammation than did
wild-type mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in
mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act
on basophils. Notably, basophils accumulating in the skin lesion showed highly upregulated expression of
Pde4b encoding the B subtype of the phosphodiesterase 4 family. Difamilast suppressed IL-4 production from
basophils activated in vitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate atopic dermatitis inflammation through the suppression of basophil IL-4 production in the skin lesion.

Keywords: Allergic inflammation, Difamilast, ERK, Mouse model, PDE4B

Investigation of the participation of the TRPV1 receptor in the irritant effect of dithranol in mice

Abstract

Dithranol is one of the most effective topical medications for treating plaque psoriasis. However, its clinical use is
limited by irritative adverse reactions to the skin, such as oedema, erythema, and pruritus, caused by poorly
understood mechanisms. Because TRPV1 activation mediates skin irritation caused by several drugs, we conducted
blind and randomised experiments in male and female C57BL/6 mice to elucidate the role of TRPV1 in
dithranol-induced irritation. Dithranol (0.01%–0.5%) or vehicle was applied topically to the right ear of the
animals. Oedema, erythema, and pruritus were monitored from 2 h to 6 days after application. Treatment with
0.5% dithranol caused oedema and erythema, but not pruritus, starting at 6 h, reaching its highest point at 1 day,
and persisting up to 6 days after treatment, mainly in male mice. The 0.1% dose induced erythema but not
oedema. Interestingly, topical application of 1% capsaicin was shown to defunctionalise TRPV1-positive fibres
and did not influence early irritation caused by dithranol (2 h–2 days). However, it increased the late phase of
irritation (5–6 days). Similarly, salicylate did not reduce the early irritation caused by dithranol but also
increased the late phase. Antagonism by SB366791 and 4-tert-butylcyclohexanol did not alter skin irritation. Our
results suggest that, contrary to our initial hypothesis, TRPV1 appears to act protectively against skin irritation
caused by dithranol, particularly in the late stage.

keywords

Neurogenic inflammation
Anthralin
TRP channels
Psoriasis

authors

Ana Merian da Silva, Marcella de Amorim Ferreira,Roberta Giusti Schran,
Debora Denardin Lückemeyer, Arthur Silveira Prudente, Juliano Ferreira

Investigation of the participation of the TRPV1 receptor in the irritant effectof dithranol in mice

Ana Merian da Silva, Marcella de Amorim Ferreira, Roberta Giusti Schran,
Debora Denardin Lückemeyer, Arthur Silveira Prudente, Juliano Ferreira

Abstract

Dithranol is one of the most effective topical medications for treating plaque psoriasis. However, its clinical use is
limited by irritative adverse reactions to the skin, such as oedema, erythema, and pruritus, caused by poorly
understood mechanisms. Because TRPV1 activation mediates skin irritation caused by several drugs, we conducted
blind and randomised experiments in male and female C57BL/6 mice to elucidate the role of TRPV1 in
dithranol-induced irritation. Dithranol (0.01%–0.5%) or vehicle was applied topically to the right ear of the
animals. Oedema, erythema, and pruritus were monitored from 2 h to 6 days after application. Treatment with
0.5% dithranol caused oedema and erythema, but not pruritus, starting at 6 h, reaching its highest point at 1 day,
and persisting up to 6 days after treatment, mainly in male mice. The 0.1% dose induced erythema but not
oedema. Interestingly, topical application of 1% capsaicin was shown to defunctionalise TRPV1-positive fibres
and did not influence early irritation caused by dithranol (2 h–2 days). However, it increased the late phase of
irritation (5–6 days). Similarly, salicylate did not reduce the early irritation caused by dithranol but also
increased the late phase. Antagonism by SB366791 and 4-tert-butylcyclohexanol did not alter skin irritation. Our
results suggest that, contrary to our initial hypothesis, TRPV1 appears to act protectively against skin irritation
caused by dithranol, particularly in the late stage.