A human and animal model-based approach to investigating the anti-inflammatory profile and potential of the 5-HT(2B) receptor antagonist AM1030

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic eczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors. Side-effects and safety concerns associated with these agents restrict their use, and new, safe treatment options are therefore needed. Recent reports suggest that serotonin, i.e. 5-hydroxytryptamine (5-HT) and the 5-HT(2) receptor family may contribute to inflammation and pruritus in the skin. The objective of this particular study was to investigate the 5HT(2B) receptor antagonist AM1030 with respect to its anti-inflammatory profile and potential. METHODS: AM1030 was tested in a set of distinct human and rodent in vitro and in vivo models, differing with respect to e.g. T cell involvement, triggering stimulus, main read-outs and route of drug administration. The in vitro systems used were staphylococcal enterotoxin A (SEA)-stimulated human peripheral blood mononuclear cells, lipopolysaccharide (LPS)-stimulated human primary monocytes, LPS-stimulated human THP-1 monocytes and LPS-stimulated mouse primary macrophages. The in vivo systems used were LPS- and SEA-induced cytokine production in the mouse, antigen-induced arthritis in the rat, glucose-6-phosphate isomerase-induced arthritis in the mouse and delayed-type hypersensitivity reaction in the mouse. In addition, different cell populations were analyzed with respect to their expression of the 5-HT(2B) receptor at the mRNA level. RESULTS: AM1030 significantly reduced both T cell-dependent and T cell-independent inflammatory responses, in vivo and in vitro. Due to the low or absent expression of the 5-HT(2B) receptor on T cell populations, the influence of AM1030 in T cell-dependent systems is suggested to be mediated via an indirect effect involving antigen-presenting cell types, such as monocytes and macrophages. CONCLUSION: Based on the wide range of model systems used in this study, differing e.g. with respect to species, T cell involvement, triggering stimuli, route of drug administration and read-outs, our results suggest a broad anti-inflammatory effect of AM1030 and identify the 5-HT(2B) receptor as a promising future target for anti-inflammatory intervention, e.g. in AD.