Inhibition of mast cell infiltration in an LL‐37‐induced rosacea mouse model using topical brimonidine tartrate 0.33% gel

Abstract

Brimonidine is a highly selective α2-adrenergic receptor agonist approved by the FDA for the treatment of rosacea. Rosacea is a major clinical disease with vasodilatation and rash on the centre of the face, and that brimonidine as a vasoconstrictor can act as a remedy for rosacea. However, there is no study of how brimonidine has an effect on rosacea-related immune cells or mechanisms in the skin to improve rosacea. In this study, we observed that clinical features of rosacea induced by LL-37 in Balb/c mice were improved after the application of brimonidine gel, and we also showed a marked decrease in the number of inflammatory cells, especially mast cells (MCs) histologically. Furthermore, we confirmed that mRnA levels of MC enzymes increased by LL-37 were reduced by brimonidine gel. To our knowledge, we first found that brimonidine has a mechanism of treating rosacea by reducing the number and mRnA levels of MC-specific enzymes, an important immune cell in the pathogenesis of rosacea. | BACKGROUNDRosacea is a common chronic inflammatory skin disease characterized by telangiectasia and flushing.[1] The erythema of rosacea is thought to result from abnormal cutaneous vasomotor activity in the central part of the face. Brimonidine tartrate 0.33% gel (Mirvaso gel; Galderma, Lausanne, Switzerland), a highly selective α2-adrenergic receptor agonist, was recently recommended for the treatment of persistent facial erythema in patients with rosacea due to its potent vasoconstrictive effects. [2] Several clinical studies have demonstrated that brimonidine rapidly improves facial flushing and erythema. [2,3] However, the molecular and histological effects of brimonidine on rosacea remain largely unknown. Although the vasoconstrictive property of brimonidine gel has been suggested to contribute to the therapeutic effect, it was assumed that not only contracting the expanded blood vessels would act on the therapeutic mechanism. | QUESTION ADDRESSEDThe aims of this study were to investigate the histological changes and gene expression levels in rosacea-like skin lesions when applied with brimonidine and to identify the role of brimonidine gel in the pathogenesis of rosacea. In this study, we investigated whether brimonidine gel could influence the number of mast cells (MCs) and mRnA levels of tryptase and chymase by evaluating the response of topical application of brimonidine gel to rosacea-like skin lesions in mice. | EXPERIMENTAL DESIGNThirty-five 7-week-old female Balb/c mice were used in this study (Dooyeol Biotech, Seoul, Korea). The experimental protocol was approved by the Animal Care Committee of Catholic University of Korea. The mice were divided into three groups: control (n=11), LL-37 (n=12), and LL-37 plus brimonidine (LL-37+ brimonidine; n=12). The mice in the LL-37 and LL-37+ brimonidine groups had LL-37 injected intradermally into shaved back skin to induce rosacea-like skin lesions.Immediately after the injection of LL-37 (40 μL), the mice in the LL-37+ brimonidine group had brimonidine tartrate 0.3...

Topical brimonidine reduces IPL‐induced erythema without affecting efficacy: A randomized controlled trial in patients with facial telangiectasias

“…Existing literature furthermore show that brimonidine reduces the concentration of vascular endothelial growth factor and thus in perspective, application of brimonidine not only once after IPL but for a longer time period may potentially maintain telangiectasia reduction . In contrast to pharmacological studies, including one in vivo study in mice that showed a significant reduction in oedema after application of brimonidine, we only found a clinical trend in favor of brimonidine to reduce IPL‐induced oedema compared to air‐cooling alone . While IPL‐induced inflammation is considered beneficial to enhance vascular damage, similar excellent clearance of >75% of telangiectasias on both facial sides in our study demonstrate that brimonidine‐induced reduction of erythema and pain does not affect IPL‐efficacy.…”

“…Topical brimonidine has been well investigated for symptomatic treatment of erythema in patients with rosacea and is approved by the FDA for this indication [21]. Pharmacological studies on brimonidine show that brimonidine causes vasoconstriction of vessels due to binding of the alpha-2-adrenergic receptor, and clinical studies on patients with rosacea found that erythema reduces at 30 minutes after application [22][23][24][25][26][27][28][29][30][31][32]. Until now, no randomized controlled trials have investigated the efficacy of brimonidine to reduce erythema after dermatological treatments using laser and energybased devices.…”

“…In 2013, topical brimonidine (Mirvaso 1 ) was approved by the Food and Drug Administration for symptomatic treatment of erythema in patients with rosacea [21]. Brimonidine is a highly selective alpha-2-adrenergic receptor agonist with potent vasoconstrictive effects [22][23][24][25]. Clinical studies performed in patients with rosacea showed that topical brimonidine reduces facial erythema significantly 30 minutes after application with a sustained efficacy up to 12 hours [26][27][28][29][30].…”

MRGPRX2 is negatively targeted by SCF and IL‐4 to diminish pseudo‐allergic stimulation of skin mast cells in culture

“…This is important in view of the relevance of this novel receptor to MC function in health and disease, including host defence against pathogens, where MCs are deemed protective partially due to MRGPRX2, and MC‐tumor interactions . Conversely, aberrant MRGPRX2 activation may contribute to neurogenic inflammation and the development of rosacea . We are at the beginning of deciphering the underpinnings of this alternative degranulation route.…”

Brimonidine tartrate 0.33 % gel for the prevention and management of hand‐foot syndrome

“…With regard to the proposed mode of action of regional cooling, our observation supports the hypothesis that its effi cacy is indeed caused mainly by local vasoconstriction rather than other effects, such as cooling-associated reduction of cell metabolism. Brimonidine tartrate can also exert immunomodulatory effects, which may further contribute to its effi cacy in the treatment of HFS [ 16 ] . While the results are encouraging, further investigation is needed with regard to the most effective formulation, the optimal concentration and the best therapeutic regimen to ensure a good pharmacokinetic profi le with the best safety profi le.…”