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Although the pathogenesis of atopic dermatitis (AD) remains to be fully deciphered, skin barrier abnormality and immune dysregulation are known to be involved. Recently, the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has also been implicated in the pathogenesis of this multifactorial chronic inflammatory skin disorder. Previously, we showed that a novel tetrapeptide, N-acetyl-Arg-Leu-Tyr-Glu (Ac-RLYE), inhibits angiogenesis and vascular permeability effectively by selectively antagonizing VEGFR-2. The current study aimed to investigate the pharmacological effect of Ac-RLYE on AD in vitro and in vivo. The in vitro experiments demonstrated that Ac-RLYE inhibited VEGF-induced vascular permeability in endothelial cells. Moreover, in an in vivo animal model of AD, Ac-RLYE relieved AD-like symptoms such as ear thickness and dermatitis severity scores and infiltration of immune cells, including mast cells and eosinophils. Ac-RLYE inhibited IgE secretion, restored the skin barrier protein filaggrin level, and markedly downregulated gene expression of AD-related Th1, Th2, and Th17 cytokines. Collectively, these findings suggest that Ac-RLYE would be useful for the treatment of AD and associated inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases. [ABSTRACT FROM AUTHOR]