Brimonidine displays anti‐inflammatory properties in the skin through the modulation of the vascular barrier function

Abstract

Background Rosacea is a chronic inflammatory skin disease. Characteristic vascular changes in rosacea skin include enlarged, dilated vessels of the upper dermis and blood flow increase. Brimonidine is approved for symptomatic relief of the erythema of rosacea. It acts by selectively binding to α2‐adrenergic receptors present on smooth muscle in the peripheral vasculature, resulting in transient local vasoconstriction. Objectives To provide further evidence of the anti‐inflammatory potential of brimonidine across preclinical models of skin inflammation and its ability to decrease the neutrophil infiltration in human skin after ultraviolet light exposure. Methods The anti‐inflammatory properties of brimonidine through modulation of the vascular barrier function were assessed using in vivo neurogenic vasodilation and acute inflammatory models and a well‐described in vitro transmigration assay. A clinical study assessed the neutrophil infiltration in human skin after exposure to UV in 37 healthy Caucasian male subjects. Results In vitro, brimonidine affects the transmigration of human neutrophils through the endothelial barrier by modulating adhesion molecules. In vivo, in the mouse, topical treatment with brimonidine, used at a vasoconstrictive dose, confirmed its anti‐inflammatory properties and prevented leucocyte recruitment (rolling and adhesion) mediated by endothelial cells. Topical pretreatment with brimonidine tartrate 0.33% gel once a day for 4 days significantly prevented neutrophil infiltration by 53.9% in human skin after exposure to UV light. Conclusion Results from in vitro, in vivo and from a clinical study indicate that brimonidine impacts acute inflammation of the skin by interfering with neurogenic activation and/or recruitment of neutrophils.

Innate Immune Dysfunction in Rosacea Promotes Photosensitivity and Vascular Adhesion Molecule Expression

“…Thus, although the mechanisms responsible for the regulation of inflammation in rosacea are not completely elucidated, these observations of adhesion molecule expression in rosacea represent an important new step in understanding the pathogenesis of this disease. Clinical relevance may be observed when considering that topical application of brimonidine, an a 2 -adrenergic receptor agonist, has also been shown to alleviate vascular inflammation by inhibiting leukocyte adhesion to the endothelial vessels in an in vivo mouse model (Bertino et al, 2018). Clinical significance may be demonstrated in the future by blocking endothelial adhesion molecule interactions with their cognate ligands on leukocytes as a strategy to improve the pro-inflammatory microenvironment in patients with multiple photosensitivity disorders.…”

Facial flushing and erythema of rosacea improved by carvedilol

“…1,5 Although the pathogenesis of rosacea is not fully understood, facial flushing and erythema is considered to be associated with dysregulation of cutaneous vascular function. 4,5,12 Topical brimonidine 0.33% gel, an approved treatment for erythema of rosacea, acts by selectively binding to α2-adrenergic receptors, resulting in transient local vasoconstriction and overstabilization. 12 However, not all patients respond well to brimonidine, and some patients have adverse reactions, such as a burning sensation or contact dermatitis.…”

“…4,5,12 Topical brimonidine 0.33% gel, an approved treatment for erythema of rosacea, acts by selectively binding to α2-adrenergic receptors, resulting in transient local vasoconstriction and overstabilization. 12 However, not all patients respond well to brimonidine, and some patients have adverse reactions, such as a burning sensation or contact dermatitis. Therefore, alternative treatment options are still necessary.…”

“…Transient or persistent erythema is the most common sign of rosacea and can cause significant physical discomfort and emotional distress 1,5 . Although the pathogenesis of rosacea is not fully understood, facial flushing and erythema is considered to be associated with dysregulation of cutaneous vascular function 4,5,12 . Topical brimonidine 0.33% gel, an approved treatment for erythema of rosacea, acts by selectively binding to α2‐adrenergic receptors, resulting in transient local vasoconstriction and overstabilization 12 .…”

Murine models of rosacea: a review

“…This model has been used as an inflammation model by Piwnica and colleagues to measure the anti‐inflammatory effect of brimonidine in vivo. In 2018, Bertino and colleagues also used 12‐O‐Tetradecanoylphorbol‐13‐acetate inflammation model to induce acute inflammation, and the first step of leucocyte recruitment into the inflammatory site was observed with intravital microscopy 38 . 12‐O‐Tetradecanoylphorbol‐13‐acetate treatment could significantly increase the number of rolling along the endothelium and adherent leucocytes in ear postcapillary venules, which could be almost completely prevented by brimonidine topical pretreatment.…”