Repeated Treatment With the Traditional Medicine Unsei-in Inhibits Substance P-Induced Itch-Associated Responses Through Downregulation of the Expression of Nitric Oxide Synthase 1 in Mice

Abstract

Abstract. Unsei-in inhibits substance P (SP)-induced scratching of mice after repeated administration. The involvement of cutaneous nitric oxide (NO) in the SP-induced scratching led us to investigate the effects of Unsei-in on the cutaneous NO system in mice. Seven-day oral administration of Unsei-in (300, but not 100, mg / kg daily) significantly inhibited scratching and the increase of cutaneous NO after intradermal SP injection. The NO synthase 1 (NOS1) inhibitor 7-nitroindazole (1 nmol / site) decreased SP-induced scratching and NO production. Repeated administration of Unsei-in (300 mg / kg) reduced the cutaneous NOS1 level. The results suggest that the inhibition of cutaneous NOS1 expression and NO production participates in the antipruritic action of Unsei-in.Keywords: Unsei-in, nitric oxide synthase 1, itch-associated response Unsei-in is a traditional medicine that is composed of Rehamanniae Radix, Paeoniae Radix, Cnidii Rhizoma, Angelicae Radix, Scutellariae Radix, Phellodendric Cortex, Coptidis Rhizoma, and Gardeniae Fructus. It is used to treat pruritic cutaneous diseases such as eczema and skin eruptions. With regard to the experimental evidence for the antipruritic effects of Unsei-in, we have recently found that although single oral administration of Unsei-in (300 and 1,000 mg / kg) does not affect substance P (SP)-induced scratching (itch-associated response), repeated administration of the dose of 300 mg / kg significantly inhibits the scratching in mice (1). In addition, the same dosage of Unsei-in significantly downregulated the expression of NK 1 tachykinin receptors in the mouse skin (1).SP acts on mast cells to release histamine, which may not be mediated by the activation of tachykinin receptors, but instead by the direct action on G protein (2). On the other hand, an intradermal injection of SP elicits scratching in mice (3), which is inhibited by the NK 1 tachykinin receptor antagonist (4), but not by the H 1 histamine receptor antagonist (5). SP-induced scratching is suppressed by the nitric oxide (NO) synthase inhibitor (6). SP increases NO production through the action on the skin, especially keratinocytes, which is inhibited by the NK 1 tachykinin receptor antagonist (6). Considering these findings, the inhibitory effect of Unsei-in on the expression of NK 1 tachykinin receptors (1) raises the possibility that the suppression of the production of NO is involved in the inhibitory effect of Unsei-in on the SP-induced scratching. To test this possibility, in the present experiments, we determined whether repeated administration of Unsei-in would affect SP-induced production of NO in the skin.SP-induced scratching is inhibited by 7-nitroindazole, an NO synthase 1 (NOS1) inhibitor (7), in mice, suggesting the involvement of NOS1 in this SP action (6). The NOS1 gene has the consensus sequence for the cyclic AMP response element (CRE) in the promoter region (8). The promoter region of the NK 1 tachykinin receptor also contains a sequence for CRE (9). Therefore, we also examined the effect ...

Severe adult atopic dermatitis successfully treated with concurrent Unseiin and standard treatment

“…showed that Unseiin inhibited substance P‐induced itch‐associated response through the suppression of neurokinin‐1 tachykinin receptor expression . They also suggested that the inhibition of cutaneous nitric oxide synthase‐1 expression and nitric oxide production participated in the antipruritic action of Unseiin . In the present case, these mechanisms might have contributed to the antipruritic effects of Unseiin followed by improvement of skin eruptions.…”

Possible Involvement of 5-Lipoxygenase Metabolite in Itch-Associated Response of Mosquito Allergy in Mice

“…In mice, nitric oxide may be as an itch enhancer and increases scratching induced by substance P (36) and medicine that decreases nitric oxide in the skin inhibits substance Pelicited scratching (37). However, the ESGM-elicited scratching was not suppressed by N G -nitro-L-arginine methyl ester at a dose that had been shown to suppress scratching induced by substance P (36), suggesting that nitric oxide is not involved in mosquito allergyassociated itching.…”

Involvement of Tryptase and Proteinase-Activated Receptor-2 in Spontaneous Itch-Associated Response in Mice With Atopy-like Dermatitis

“…Protein extraction, electrophoresis, and membrane transfer were done as described (12). The transferred membrane was reacted with anti-PAR 2 monoclonal antibody (SAM-11, 1:500; Santa Cruz Biotechnology) and anti-β-actin monoclonal antibody (1:5,000, Sigma).…”