journal clb 27-3-2015

Gamisasangja-tang suppresses pruritus and atopic skin inflammation in the NC/Nga murine model of atopic dermatitis

Abstract

Ethnopharmacological relevance

Gamisasangja-tang (GST) is a traditional herbal formula prescribed for patients with intractable pruritus in association with various inflammatory skin diseases. To evaluate the effects of GST on pruritic skin inflammation and investigate its cellular and molecular mechanisms.

Materials and methods

We orally administered GST to NC/Nga (NC) mice, an animal model of atopic dermatitis. Scratching frequency and the dermatitis index were evaluated, and histological examination was performed using hematoxylin and eosin and toluidine blue staining. The levels of interleukin (IL)-31 and T-helper cell type 2 (TH2) cytokines were determined in both the dorsal skin and cultured splenocytes by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum levels of chemokines and immunoglobulin E (IgE) were determined by ELISA. Changes in the inflammatory cell population were analyzed by a hemocytometer.

Results

GST significantly lowered scratching frequency and inhibited increases in dermatitis index, thickness of epidermis/dermis and infiltration of chemokine (C-C motif) receptor 3 (CCR3)+ and cluster of differentiation (CD)117+/FcεRIα (Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide)+ cells in atopic skin. Both IL-31 mRNA expression and production were significantly reduced by GST, which was accomrease in the levels of IL-4, IL-5, and IL-13. Further, GST treatment suppressed the secretion of eotaxin, TARC (thymus and activation-regulated chemokine), IgE, and increases in the number of basophils and eosinophils in the blood.

Conclusion

GST may have potential as an effective treatment for pruritic skin disease such as atopic dermatitis

gamisasangja tang

Journal club 2015.3.20

Nalfurafine suppresses pruritogen– and touch-evoked scratching behavior in models of acute and chronic itchin mice.

Abstract

The kappa-opioid agonist, nalfurafine, has been approved in Japan for treatment of itch in patients with chronic kidney disease. We presently investigated if systemic administration of nalfurafine inhibited ongoing or touch-evoked scratching behavior (alloknesis) following acuteintradermal injection of histamine or the non-histaminergic itch mediator, chloroquine, in mice. We also investigated if nalfurafine suppressed spontaneous or touch-evoked scratching in an experimental model of chronic dry skin itch. Nalfurafine reduced scratching evoked by histamine and chloroquine. Following acute histamine, but not chloroquine, low-threshold mechanical stimuli reliably elicited directed hindlimb scratchingbehavior, which was significantly attenuated by nalfurafine. In mice with experimental dry skin, nalfurafine abolished spontaneous scratching but had no effect on alloknesis. Nalfurafine thus appears to be a promising treatment for acute itch as well as ongoing itch of dry skin.

Journal Club 2015/3/12

TRPA1-Dependent Pruritus in IL-13–Induced Chronic Atopic dermatitis

TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis.

Abstract

Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13-transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.

journal club 2015-03-06

5-HT3 receptors antagonists reduce serotonin-induced scratching in mice

Running title: 5-HT3 receptors mediate serotonin-induced scratching

fcp12112

Sattar Ostadhadi a,b, Nastaran Kordjazy a,b, Arya Haj-Mirzaian a,b, Parvin Mansouri c, Ahmad Reza Dehpour a,b*

a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

b Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

c Skin and Stem cell Research Center, Tehran University of Medical Sciences, Tehran, Iran

* Corresponding author:

Prof. Ahmad Reza Dehpour, PharmD, PhD, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. Tel: +98 21 88973652, fax: + 98 21 66402569, e-mail: dehpoura@sina.tums.ac.ir

 

ABSTRACT

Serotonin (5-hydroxytryptamine, 5-HT) acts as a pruritogen in humans and animals, but the mechanisms of action through that serotonin induces itch-response have not been extensively discovered. In our study, we attempted to investigate the role of 5-HT3 receptors in scratching behavior due to intradermal serotonin injection. Intradermal injection of serotonin (14.1–235 nmol/site) into the nape of the neck of mice was performed to elicit itch. Scratching behavior was evaluated by measuring the number of bouts during 60 minutes after injection. We evaluated the effect of intraperitoneal pretreatment with ondansetron and tropisetron (0.1, 0.3, and 1 mg/kg) on itch induced by serotonin. Also, intradermal ondansetron and tropisetron at doses 50, 100, and 200 nmol/site were concurrently administrated with serotonin. Serotonin produced a significant enhancement in scratching at dose 141 nmol/site. Concurrent administration of ondansetron (50, 100, and 200 nmol/site) and tropisetron (100 and 200 nmol/site) with serotonin reduced scratching activity compared to the animals that only received serotonin. Also, pretreatment with intraperitoneal ondansetron and tropisetron (0.3 and 1 mg/kg) 30 min before serotonin attenuated the itch response. We showed that the scratching induced by intradermal serotonin is mediated by 5-HT3 receptors subtype. It can be concluded that 5-HT3 may play a role in mediating serotonin-associated itch responses, and we introduce 5-HT3 receptors as possible targets for antipruritic agents.

Key words: Scratching; Serotonin (5-HT); 5-HT3 antagonists; Mice

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