miRNA-203b-3p Induces Acute and Chronic Pruritus through 5-HTR2B and TRPV4.

Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch through transient receptor potential channels signaling are poorly understood. In this study, we show that genetic deletion or pharmacological antagonism of TRPV4 attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several microRNAs, including the miR-203b-3p, which induced a calcium ion response in rodent dorsal root ganglion neurons and scratching behavior in mice through 5-HTR2B activation and the protein kinase C‒dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular microRNA that can behave as an itch promoter through 5-HTR2B and TRPV4.

Anti-inflammatory and anti-pruritic effects of Chi-Huang Solution in a murine model of allergic contact dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: In treating atopic dermatitis, multi-mode management is adopted, including trying to avoid the allergens, controlling and preventing secondary infections, and using drugs to control itching. At present, most of the commonly used anti-pruritic drugs in the clinic are single-target and lead to serious side effects. Many studies have shown that a variety of traditional Chinese medicines have significant anti-inflammatory and anti-pruritic effects, and have the characteristics of multiple components, multiple targets, and multiple effects. AIM OF THE STUDY: The study aimed to explore the anti-inflammatory and anti-pruritic effects of the Chi-Huang Solution in a murine model of Allergic contact dermatitis (ACD). This study considers the effectiveness of the Chi-Huang Solution for external use on skin to provide an experimental basis for the clinical development and application of Chinese medicine and related preparations for Canine atopic dermatitis (CAD). MATERIALS AND METHODS: Forty-two male SPF C57BL/6 mice were randomly divided into control group (n = 6), ACD model group (n = 6), HAC control group (n = 6), and 4 Chi-Huang Solution groups (n = 6 in each group). With SADBE induce the murine model of ACD chronic pruritus, and initially evaluate whether the model is successful by counting scratching behavior, measuring the skin fold thickness and skin lesion score within 1 h. After treating the ACD model mice with deionized water, HAC, 1CH, 2CH, 3CH, and 4CH for 7 days, behavioral changes were used to evaluate the anti-pruritic effect. The skin fold thickness, skin lesion score, and spleen index were used to evaluate the anti-inflammatory effect of the Chi-Huang Solution. H.E. staining was used for the epidermal thickness measurement and pathological evaluation. RT-qPCR was used to analyze the mRNA expression of related inflammatory factors such as IL-1ß, TNF-α, IL-33, IL-4, IL-17A, CXCL10, and its receptor CXCR3 in the skin of the lesion site, as well as to detect the mRNA expression of pruritus-related genes such as TRPV1, TRPA1, and GRP in DRG. RESULTS: After the treatment of low-dose (0.1 g/mL) and medium-dose (0.2 g/mL) Chi-Huang Solution, the scratching times both decreased significantly (P < 0.05), meanwhile the medium-dose Chi-Huang Solution had an obvious effect on reducing scratches/scab score (P < 0.05). Moreover, no matter what dose it takes, all Chi-Huang Solution can alleviate the epidermal thickening (P < 0.05) and the infiltration of mast cells in the ACD murine model of ACD. It is worth mentioning that the count of mast cells in the dermis was significantly down-regulated after the treatment of medium-dose Chi-Huang Solution (P < 0.005). Furthermore, Chi-Huang Solution can significantly down-regulate the mRNA expression of related inflammatory factors in the skin, and reduce the mRNA expression of pruritus-related genes, such as TRPA1, TRPV1, and GRP in the spinal cord. CONCLUSIONS: The results indicated that Chi-Huang Solution for external use exhibits significant anti-inflammatory and anti-pruritic effects on SADBE-induced ACD chronic pruritus murine models. Chi-Huang Solution might emerge as an effective drug for the treatment of CAD and high-dose Chi-Huang Solution (0.4 g/ml) has better comprehensive effects.

PLACK syndrome is potentially treatable with intralipids.

We describe an 11-year-old girl with PLACK Syndrome (peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads), who was found to have a novel homozygous variant in CAST, the pathogenicity of which was confirmed using blood-derived RNA. There is no established treatment for PLACK syndrome. However, we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids, which prompted us to consider a potential treatment strategy. Indeed, we initiated this patient on intravenous lipid infusion (Vitalipid®; an emulsion of fat-soluble vitamins and lipofundin-MCT/LCT 20%) and the response was dramatic. Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement. PLACK syndrome is a very rare genodermatosis and only six families have been described to date with pathogenic CAST variants. This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition. The remarkable response we report and the relative safety of the intervention should prompt healthcare providers who care for PLACK syndrome patients to explore this as a potential treatment strategy in future studies.

Matrine inhibits itching by lowering the activity of calcium channel.

Sophorae Flavescentis Radix (SFR) is a medicinal herb with many functions that are involved in anti-inflammation, antinociception, and anticancer. SFR is also used to treat a variety of itching diseases. Matrine (MT) is one of the main constituents in SFR and also has the effect of relieving itching, but the antipruritic mechanism is still unclear. Here, we investigated the effect of MT on anti-pruritus. In acute and chronic itch models, MT significantly inhibited the scratching behavior not only in acute itching induced by histamine (His), chloroquine (CQ) and compound 48/80 with a dose-depended manner, but also in the chronic pruritus models of atopic dermatitis (AD) and acetone-ether-water (AEW) in mice. Furthermore, MT could be detected in the blood after intraperitoneal injection (i.p.) and subcutaneous injection (s.c.). Finally, electrophysiological and calcium imaging results showed that MT inhibited the excitatory synaptic transmission from dorsal root ganglion (DRG) to the dorsal horn of the spinal cord by suppressing the presynaptic N-type calcium channel. Taken together, we believe that MT is a novel drug candidate in treating pruritus diseases, especially for histamine-independent and chronic pruritus, which might be attributed to inhibition of the presynaptic N-type calcium channel.

Topical Application of Angelica sinensis Improves Pruritus and Skin Inflammation in Mice with Atopic Dermatitis-Like Symptoms.

Angelica sinensis (AS) is one of the most popular medicinal foods used as a hematopoietic herb and also traditionally applied topically for skin disorders. However, the effectiveness of AS on atopic dermatitis (AD) has not been reported yet. This study was conducted to evaluate the antipruritic and anti-inflammatory effects of AS on regulating AD-related mediators in DNCB (2,4-dinitrochlorobenzene)-induced mice. AS was topically applied to the dorsal skin of DNCB-challenged mice for 11 days. Alteration of skin thickness was measured for assessment of histological improvement. In addition, the number of mast cells, the level of serum immunoglobulin E (IgE), the counting of scratching behavior, and the expression of substance P were evaluated. Also, the expressions of cytokines, nuclear factor κB (NF-κB), phospho-IκBα, and mitogen-activated protein kinases (MAPKs) were measured for evaluating the improvement of skin inflammation. The repeated treatment of AS significantly inhibited the skin thickness, the number of mast cells, and the level of serum IgE. Moreover, AS significantly suppressed the increased scratching behavior and the expression of substance P compared to the DNCB group. Topical application of AS also reduced the level of cytokines (IL-4, IL-6, TNF-α, and IFN-γ) as well as the expressions of NF-κB, phospho-IκBα, and phospho-MAPKs in the dorsal skin. The results of our study suggest that topical application of AS might have efficacy for modulating pruritus and inflammation in AD. Further studies are required to further characterize the mechanism of actions of AS.

Mechanisms of itch evoked by ß-alanine.

ß-Alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, ß-alanine elicited itch-associated behavior that requires MrgprD, a G-protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to ß-alanine, heat, and mechanical noxious stimuli but do not respond to histamine. In humans, intradermally injected ß-alanine induced itch but neither wheal nor flare, suggesting that the itch was not mediated by histamine. Thus, the primary sensory neurons responsive to ß-alanine are likely part of a histamine-independent itch neural circuit and a target for treating clinical itch that is unrelieved by anti-histamines.

Evaluation of the effects of anti-pruritic drugs on scratch responses using histamine H1 receptor-deficient mice.

The effects of anti-pruritic drugs on scratching behavior associated with passive cutaneous anaphylaxis in histamine H(1) receptor-deficient and wild-type mice were studied. Passive sensitization with mouse monoclonal anti-dinitrophenyl-immunoglobulin E (IgE) resulted in an increase in the incidence of scratching behavior induced by intravenous injection of dinitrophenyl-ovalbumin in both wild-type and histamine H(1) receptor-deficient mice. The histamine H(1) receptor antagonist diphenhydramine inhibited scratching behavior induced by antigen in passively sensitized wild-type mice, whereas no effect was observed in histamine H(1) receptor-deficient mice. On the other hand, oxatomide inhibited scratching behavior in both mice, although the effect in wild-type mice was more potent than that in histamine H(1) receptor-deficient mice. Tranilast inhibited scratching behavior with the same potency in both mice. We concluded that the scratching behavior associated with passive cutaneous anaphylaxis involves not only histamine H(1) receptors but also other chemical mediators. Furthermore, the results of the present study indicated that oxatomide has an antagonistic effect on histamine H(1) receptors as well as anti-pruritic effect in vivo.

Analysis of the spontaneous scratching behavior by NC/Nga mice: a possible approach to evaluate antipruritics for subjects with atopic dermatitis.

We investigated the spontaneous scratching by NC/Nga mice to design a new method for evaluating the itch of subjects with atopic dermatitis. The numbers of scratchings in various strains of mice were classified based on the duration of the scratching. Prolonged scratching was frequent in skin-lesioned NC/Nga mice, but not in ICR, BALB/c and non-lesioned NC/Nga mice. Pretreatment with dexamethasone or tacrolimus significantly suppressed long-duration scratching in NC/Nga mice but did not suppress short-duration scratching induced by ovalbumin active cutaneous anaphylaxis in BALB/c mice and in ICR mice subcutaneously injected with histamine. In contrast, pretreatment with chlorpheniramine or ketotifen significantly suppressed short-duration scratching induced by ovalbumin active cutaneous anaphylaxis in BALB/c mice and in ICR mice subcutaneously injected with histamine, but not long-duration scratching seen in NC/Nga mice. These findings indicate that the mechanism of spontaneous scratching in NC/Nga mice differs from that induced by several pruritogen injections. This new method shows good correlation with the therapeutic activity of drugs in cases of atopic dermatitis in humans and may serve as a useful model for evaluating antipruritic drugs and for studying mechanisms involved in atopic dermatitis.