Yokukansan, a traditional Japanese medicine, adjusts glutamate signaling in cultured keratinocytes.

Glutamate plays an important role in skin barrier signaling. In our previous study, Yokukansan (YKS) affected glutamate receptors in NC/Nga mice and was ameliorated in atopic dermatitis lesions. The aim of this study was to assess the effect of YKS on skin and cultured human keratinocytes. Glutamate concentrations in skin of YKS-treated and nontreated NC/Nga mice were measured. Then, glutamate release from cultured keratinocytes was measured, and extracellular glutamate concentrations in YKS-stimulated cultured human keratinocytes were determined. The mRNA expression levels of NMDA receptor 2D (NMDAR2D) and glutamate aspartate transporter (GLAST) were also determined in YKS-stimulated cultured keratinocytes. The glutamate concentrations and dermatitis scores increased in conventional mice, whereas they decreased in YKS-treated mice. Glutamate concentrations in cell supernatants of cultured keratinocytes increased proportionally to the cell density. However, they decreased dose-dependently with YKS. YKS stimulation increased NMDAR2D in a concentration-dependent manner. Conversely, GLAST decreased in response to YKS. Our findings indicate that YKS affects peripheral glutamate signaling in keratinocytes. Glutamine is essential as a transmitter, and dermatitis lesions might produce and release excess glutamate. This study suggests that, in keratinocytes, YKS controls extracellular glutamate concentrations, suppresses N-methyl-D-aspartate (NMDA) receptors, and activates glutamate transport.

Retrospective cohort study on combination therapy with the histamine H2-receptor antagonist lafutidine for antihistamine-resistant chronic urticaria.

We conducted a retrospective cohort study evaluating the efficacy and usefulness of the addition of lafutidine, a novel histamine H2-receptor antagonist, in treatment of patients with idiopathic chronic urticaria whose disease was not well controlled with histamine H1-receptor antagonists. Based on the assessment of global improvement, moderate or better improvement was achieved in 39 of 46 patients (85%) after 1-3 weeks of additional administration of lafutidine and 35 patients (76%) after 3 months. No incidence of drug-related adverse reactions was reported in any patient. Lafutidine was rated as useful or better in 34 patients (74%) after 3 months of treatment. The usefulness of the drug was not affected by differences in background factors, such as disease duration, previous treatment duration and the number of concomitant H1-receptor antagonists. Lafutidine appears to be a promising addition to histamine H1-receptor antagonist therapy for the treatment of chronic urticaria resistant to treatment with H1-receptor antagonists alone.

Ameliorating effect of Yokukansan on the development of atopic dermatitis-like lesions and scratching behavior in socially isolated NC/Nga mice.

Yokukansan (YKS) has been used in Japan as a remedy for neurosis, insomnia, and children with night crying. In a previous study, we reported that YKS controls scratching behavior and inhibits the development of atopic dermatitis (AD)-like lesions in NC/Nga mice. In this study, we investigated the effects of YKS on the development of AD-like lesions in socially isolated NC/Nga mice compared with the effects of fexofenadine and elucidated the mechanism of the ameliorating effect of YKS on the skin lesions. Ten-week-old male NC/Nga mice were divided into three groups (n = 5/group): the conventional control, the YKS-treated, and the fexofenadine-treated groups, and were kept isolated under conventional conditions for 6 weeks. Measurements were made of dermatitis scores and transepidermal water loss (TEWL), scratching and grooming behaviors. Immunohistochemistry and mRNA levels were also evaluated. We performed similar experiments under specific pathogen free (SPF) conditions that served as a SPF control. YKS and fexofenadine inhibited the aggravation of skin lesions and decreased TEWL, but only YKS decreased the numbers of scratching and pathologic grooming behaviors. Immunohistochemistry and RT-PCR revealed that N-methyl-D: -aspartate (NMDA) receptor expression was increased in the skin of conventional control mice and was decreased in YKS-treated mice. Glutamate transporter-1 (GLT-1) mRNA levels were decreased in the skin of conventional control mice and were increased in YKS-treated mice. The results indicate that YKS ameliorates AD-like skin lesions in NC/Nga mice through a mechanism distinct from that of fexofenadine. Furthermore, the effects of YKS are suggested to be mediated via glutamate signaling in the skin lesions.

Oral administration of Yokukansan inhibits the development of atopic dermatitis-like lesions in isolated NC/Nga mice.

BACKGROUND: Increasing evidence suggests that stress can trigger and exacerbate atopic dermatitis (AD). Psychotherapy is becoming more important in the treatment of AD patients. Yokukansan (YKS, Yi-Gan San in Chinese), a traditional Japanese medicine, has been widely utilized in the treatment of neurosis, insomnia and anxiety especially in Asian countries. Furthermore, it was reported that YKS inhibited skin lesions in socially isolated mice but not in group-housed mice. Therefore, in the present study it was investigated whether or not YKS was effective in the treatment of AD using socially isolated NC/Nga mice. OBJECTIVE: The present study was designed to assess the effect of YKS on the development of AD-like lesions in socially isolated NC/Nga mice to obtain information about its usefulness in the treatment of AD. METHODS: Ten-week-old male NC/Nga mice were socially isolated under conventional conditions. YKS was administered orally to mice at the dose of 0.5% or 1.0% together with diet. The efficacy of YKS was evaluated by assessing skin lesion severity, scratching behaviors, skin hydration, and infiltration of inflammatory cells in the skin. Grooming behaviors evoked by social isolation stress and serum corticosterone levels were also measured. RESULTS: Oral administration of YKS to socially isolated NC/Nga mice resulted in the inhibition of exacerbation of AD-like skin lesions. It seemed that the inhibition of exacerbation of AD-like skin lesions observed in NC/Nga mice might be due to suppression of the scratching and grooming behaviors, inhibition of the infiltration of mast cells and eosinophils, and retention of humidity in the skin. Serum corticosterone levels were also significantly inhibited in the 1%-YKS-treated mice as compared with those of the control mice. There were no significant differences in the levels of serum total IgE and nerve growth factor (NGF) between the YKS-treated mice and the non-treated control mice. CONCLUSION: YKS inhibited the development of AD-like skin lesions in socially isolated NC/Nga mice by suppressing scratching and infiltration of inflammatory cells in the skin. These results indicate that YKS possesses an anti-itching property, and its anti-itching may be partly through attenuation on social isolation stress. It is expected that YKS might provide an effective alternative therapy for AD in human patients.