The new external drug for the treatment of psoriasis based on inhibition of serine proteases

Abstract

Background: Psoriasis is a chronic inflammatory immune-mediated disease characterized by an increased rate of keratinocyte division. The results of recent studies have made it possible to establish that the cytokines of the IL-36 family occupy a significant place in the initiation and regulation of the inflammatory process in psoriasis. IL-36 is in an inactive form and proteolytic processing is required for its activation in the skin, which is possible with the participation of neutrophilic serine proteases. Localization of these enzymes in the upper layers of the epidermis suggests the clinical efficacy of a topical targeted drug that inhibits serine proteases, sivelestat. On the basis of this active substance, we have created a drug in an external dosage form and conducted an experimental study of its effectiveness on a laboratory model of psoriasis. Aims: to evaluate the therapeutic efficacy of sivelestat in a laboratory model of imiquimod-induced psoriasis. Materials and methods: In the experiment, 40 inbred BALB/c mice were used, which were randomized into 4 groups of 10 each. An imiquimod-induced model of psoriasis was used. Mice of group No. I - without therapy (control), No. II - ointment (vaseline) containing 1% sivelestat, No. III - cream (lanolin + olive oil + water in equal proportions) containing 1% sivelestat, No. IV - betamethasone cream dipropionate 0.05%. Clinical assessment of skin rashes was performed using the PASI-modified method (mPASI), as well as histological and immunohistochemical examination of the skin. Results: When evaluating clinical manifestations, it was found that the total mPASI index when using sivelestat cream decreased by 50%, and sivelestat ointment - by 36%. The histological examination showed that the thickness of the epidermis in the groups where the therapy was applied was 2.4-3.6 times less than in the control group. An immunohistochemical study of the skin found that after treatment with sivelestat, the number of CD3 + cells in the skin was 1.8-2.2 times less, and the level of proliferative activity (Ki-67 + cells) was 2.3-2.9 times less. lower than in the group without therapy Conclusions: On a laboratory model of imiquimod-induced psoriasis, it was found that a serine protease inhibitor (sivelestat) has a therapeutic efficacy comparable to a strong topical glucocorticosteroid drug (betamethasone dipropionate 0.05%). A pronounced resolution of the elements of the skin rash, a reduction in the thickness of the epidermis, a decrease in skin infiltration with T-lymphocytes and a normalization of the rate of cell division of the epidermis and dermis are shown. Suppression of the activity of IL-36-mediated inflammation in the skin by means of topical inhibitors of serine proteases is a promising new direction in the treatment of patients with psoriasis.

Keywords

• psoriasis
• treatment
• sivelestat
• serine proteases
• psoriasis model
• il-36