Diosmin nanocrystals alleviate Imiquimod induced psoriasis in rats via modulating TLR7,8/ NF-κB/micro RNA-31, AKT/mTOR/P70S6K milieu and Tregs / Th17 balance

Abstract

Diosmin is a flavonoidal compound characterized by highly challenging physicochemical properties. There wasn’t enough attention paid for using diosmin topically in spite of its strong anti-inflammatory and anti-oxidant properties. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Evaluation of different stabilizers with different concentrations to achieve the most stable nanocrystals was studied. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in weight ratio (diosmin:polymer 1:1) could reach the desired particle size (276.9 ± 16.49 nm); provided the promising colloidal properties and higher drug release profile. In-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystals gel using 3 different doses and diosmin powder gel in alleviating imiquimod induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystals gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most significant mitigation in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels (IL17A, IL23, and IL22). Furthermore, it was capable of maintaining balance between Th17 and Treg cells by decreasing the immunohistochemical expression of RORγ and increasing that of FOXP3. Moreover, it tackled TLR7/8/NF-κB, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (negative regulator of NF-κB) expression in psoriatic skin tissues. Also, it abrogated the tissue expression of PCNA, BCL-2 and miRNA-31 level. This highlights the role of diosmin nanocrystals gel in tackling imiquimod induced psoriasis in rats via modulating TLR7,8/NF-κB/miRNA-31, AKT/mTOR/P70S6K milieu and Tregs/Th17 balance. Therefore, it is suggested that diosmin nanocrystals gel could be a novel promising therapy for psoriasis.