Potential therapeutic application of 2,4,6-Trihydroxy- 3- Geranylacetophenone as a mast cell stabiliser for Atopic Dermatitis-like skin lesions In Vivo

Atopic dermatitis (AD) is a relapsing inflammatory skin disease that lacks a definitive cure due to its complexed pathogenesis. 2, 4, 6-trihydroxy-3-geranylacetophenone (tHGA) is an active compound isolated from a local shrub called Melicope ptelefolia or locally known as “tenggek burung”. Previous studies revealed tHGA's ability to attenuate allergic airway inflammation, asthma and inhibition of passive systemic anaphylaxis in both cellular and animal models, via IgE-mediated mast cell degranulation. This study aimed to investigate the potential therapeutic application of tHGA as an oral and topical agent for alleviating DNCB-induced atopic dermatitis- like skin lesions in murine models. Male BALB/c mice were sensitized and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the orally treated groups received three doses of tHGA - 20, 40 and 80 mg/kg, three times per week for two weeks. For the topical treatment of tHGA, mice were applied with three doses of tHGA - 0.2%, 1% and 5% once daily for twelve days. The mice were sacrificed on day 34 and their dorsal skin and blood samples were collected for analysis. DNCB application is known to trigger excessive scratching behaviour, which causes damage to the physical skin barrier. The scratching latency was significantly reduced in all doses of orally and topically administered tHGA. Oral and topical application of tHGA exhibited similar results for SCORAD as the medium (40 mg/kg and 1%) and highest doses (80 mg/kg and5%) managed to significantly improve the dermatitis score. Measurement of epidermal thickness showed that the orally treated tHGA (40 and 80 mg/kg) was able to significantly reduce the thickness in comparison to the topical application of tHGA, where all doses exhibited significant reduction. Eosinophils act as pro-inflammatory cells as they secrete various pro-inflammatory mediators and the effect of orally and topically treated tHGA on eosinophils can be seen as all doses of tHGA of both routes significantly reduced both blood and tissue eosinophilia. The effects of oral and topical administrations of tHGA on the infiltration and degranulation of mast cells were further evaluated to prove mast cells’ influence on inflammation. The results showed that tHGA at all doses of both routes significantly reduced the infiltration of mast cells. In addition, degranulation of mast cells demonstrated significant decrease for all tested doses of orally treated tHGA whereas, for the topical application of tHGA, medium and highest doses (1% and 5%) exhibited significant reduction. All doses of orally treated tHGA displayed alleviation in the level of IL-4 in the skin lysate although only 80 mg/kg had a significant effect as compared to the topically treated tHGA where all doses showed significant alleviation. tHGA systemic inhibitory effect for serum IL-4 can be seen as all tested doses; 20, 40 and 80 mg/kg, managed to significantly decrease the level of IL-4 in the serum. All tested doses of oral administration and topical application of tHGA demonstrated significant attenuation of serum IgE level. Taken together, these findings indicate that tHGA exhibit therapeutic potential both as oral and topical agents in ameliorating atopic dermatitis in a murine model.

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