Contribution of α4β1 integrin to the antiallergic effect of levocabastine
Department of Medicine, Health Science Campus, University of Toledo, OH, USA. Biochemical pharmacology
(Impact Factor: 5.01).
10/2008; 76(6):751-62. DOI: 10.1016/j.bcp.2008.07.007
Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. The adhesion molecule integrin alpha(4)beta(1) is expressed in eosinophils; it interacts with the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) in vascular endothelial cells and contributes to eosinophil activation and infiltration in AC. This study provides evidence that in a scintillation proximity assay levocabastine (IC(50) 406 microM), but not the first-generation antihistamine chlorpheniramine, displaced (125)I-FN binding to human integrin alpha(4)beta(1) and, in flow cytometry analysis, levocabastine antagonized the binding of a primary antibody to integrin alpha(4) expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the alpha(4)beta(1) integrin and prevents eosinophil adhesion to VCAM-1, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects alpha(L)beta(2)/ICAM-1-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of alpha(4)beta(1) integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in AC.
Available from: Paolo Govoni
- "Slides were desiccated in xylene, stained with hematoxylin–Biebrich scarlet solution, differentiated in 1% acid alcohol, and subsequently stained with lithium carbonate. Eosinophil granules stain red-orange.33 The number of eosinophils in each field was counted under light microscopy (500× magnification). "
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Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6–10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines.
In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA)-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5), C-C motif ligand 11 (CCL11), and interleukin-8 (IL-8) and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α).
Mapracorat, administered into the conjunctival sac of OVA-sensitized guinea pigs 2 hours after allergen exposure, was effective in reducing clinical signs, eosinophil infiltration, and eosinophil peroxidase activity in the guinea pig conjunctiva; furthermore, it reduced conjunctival mRNA levels and protein expression of both CCL5 and CCL11. Mapracorat was more effective than dexamethasone in increasing, in conjunctival sections of OVA-treated guinea pigs, apoptotic eosinophils.
Mapracorat displays anti-allergic properties in controlling the late phase of ocular allergic conjunctivitis and is a promising candidate for the topical treatment of allergic eye disorders.
Drug Design, Development and Therapy 06/2014; 8:745-57. DOI:10.2147/DDDT.S62659 · 3.03 Impact Factor
Available from: Andrea Leonardi
- "Levocabastine 0.05% eye drops alone, instilled four times daily for 3 months, was effective, safe, and well tolerated by patients with VKC; however, it was less effective than lodoxamide  or NAAGA . Interestingly, in an animal model, levocabastine reduced the clinical aspects of the late-phase reaction and the conjunctival expression of alpha(4)beta(1) integrin by reducing infiltration of eosinophils . "
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ABSTRACT: Vernal keratoconjunctivitis (VKC) is a relatively rare, chronic form of ocular allergy that can potentially cause severe visual complications. Affecting mainly children and young adults, it is an IgE- and T cell-mediated disease, leading to a chronic inflammation in which eosinophil, lymphocyte and structural cell activation are involved. Treatment of VKC requires a multiple approach that includes conservative measures and pharmacologic treatment. Patients and parents should be made aware of the long duration of disease, its chronic evolution and possible complications. Treatment should be based on the duration and frequency of symptoms and the severity of corneal involvement. Mast cell stabilizers and antihistamines have been proven to be effective for the treatment of mild to moderate forms of VKC. In the most severe cases, topical steroids can be used as rescue medication to reduce conjunctival and corneal inflammation. Immunomodulators that have been investigated for VKC treatment include topical ocular preparations of cyclosporine A and tacrolimus. Topical cyclosporine A has been proven to be effective in the long-term treatment of VKC, significantly improving signs and symptoms without significant side effects.
12/2013; 2(2):73-88. DOI:10.1007/s40123-013-0019-y
Available from: Samantha Deianira Dattoli
- "Similarly, levocabastine affects α L β 2 /ICAM-1-mediated adhesion of Jurkat cells. In a model of allergic conjunctivitis, levocabastine eye drops reduced the clinical aspects of the late phase reaction and the conjunctival expression of α 4 β 1 integrin by reducing eosinophil infiltration (Qasem et al., 2008). These data confirm that levocabastine is an antihistamine with multiple mechanisms of action that inhibit the early and late phases of allergic reaction (Bielory et al., 2005). "
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ABSTRACT: Considerable evidence indicates that eosinophils are important effectors of ocular allergy. Increased worldwide prevalence of allergic eye pathologies has stimulated the identification of novel drug targets, including eosinophils and adhesion molecules. Accumulation of eosinophils in the eye is a key event in the onset and maintenance of allergic inflammation and is mediated by different adhesion molecules. Antihistamines with multiple mechanisms of action can be effective during the early and late phases of allergic conjunctivitis by blocking the interaction between β(1) integrins and vascular cell adhesion molecule (VCAM)-1. Small molecule antagonists that target key elements in the process of eosinophil recruitment have been identified and reinforce the validity of α(4)β(1) integrin as a therapeutic target. Glucocorticoids are among the most effective drugs for ocular allergy, but their use is limited by adverse effects. Novel dissociated glucocorticoids can prevent eosinophil accumulation and induce apoptosis of eosinophils, making them promising candidates for ophthalmic drugs. This article reviews recent understanding of the role of adhesion molecules in eosinophil recruitment in the inflamed conjunctiva along with effective treatments for allergic conjunctivitis.
Frontiers in Pharmacology 12/2012; 3:203. DOI:10.3389/fphar.2012.00203 · 3.80 Impact Factor
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