Effects of latanoprost, timolol and GLC756, a novel dopamine D(2) agonist and D(1) antagonist on LTC(4) release after rat mast cell activation.
ABSTRACT Mast cells participate in ocular allergic inflammation by releasing biologically active mediators. Leukotrienes are released from activated mast cells via an IgE-dependent mechanism, and play a crucial role in ocular allergic inflammation. In this study, the effect of three topical antiglaucoma drugs, that is, latanoprost, timolol and GLC756, a novel dopamine D(2) agonist and D(1) antagonist, on leukotriene C(4) (LTC(4)) release after rat mast cell activation was examined.
A rat basophilic leukaemia RBL-2H3 mast cell line was activated via IgE/anti-IgE. Rat mast cells were incubated with latanoprost, timolol, or GLC756 at concentrations of 0.1, 1, 10 and 30 microM. LTC(4) concentration in supernatant was assessed 5 h post activation by EIA.
Compared with controls, timolol showed no relevant effect on LTC(4) release, 5 h after mast cell activation. Latanoprost and GLC756, in contrast, revealed an inhibitory effect on LTC(4) release, which was dose-related and statistically significant at the concentrations of 10 and 30 microM.
The results of this study suggest that timolol has no significant influence on LTC(4) release from activated mast cells. By contrast, latanoprost and GLC756 inhibited LTC(4) release, suggesting a possible anti-inflammatory effect on ocular allergic inflammatory processes in topical glaucoma medication.
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ABSTRACT: Clinical reports indicate that patients with allergy/asthma commonly have associated symptoms of anxiety/depression. Anxiety/depression can be reduced by 5-hydroxytryptophan (5-HTP) supplementation. However, it is not known whether 5-HTP reduces allergic inflammation. Therefore, we determined whether 5-HTP supplementation reduces allergic inflammation. We also determined whether 5-HTP decreases passage of leukocytes through the endothelial barrier by regulating endothelial cell function. For these studies, C57BL/6 mice were supplemented with 5-HTP, treated with ovalbumin fraction V (OVA), house dust mite (HDM) extract, or IL-4, and examined for allergic lung inflammation and OVA-induced airway responsiveness. To determine whether 5-HTP reduces leukocyte or eosinophil transendothelial migration, endothelial cells were pretreated with 5-HTP, washed and then used in an in vitro transendothelial migration assay under laminar flow. Interestingly, 5-HTP reduced allergic lung inflammation by 70-90% and reduced antigen-induced airway responsiveness without affecting body weight, blood eosinophils, cytokines, or chemokines. 5-HTP reduced allergen-induced transglutaminase 2 (TG2) expression and serotonylation (serotonin conjugation to proteins) in lung endothelial cells. Consistent with the regulation of endothelial serotonylation in vivo, in vitro pretreatment of endothelial cells with 5-HTP reduced TNF-α-induced endothelial cell serotonylation and reduced leukocyte transendothelial migration. Furthermore, eosinophil and leukocyte transendothelial migration was reduced by inhibitors of transglutaminase and by inhibition of endothelial cell serotonin synthesis, suggesting that endothelial cell serotonylation is key for leukocyte transendothelial migration. In summary, 5-HTP supplementation inhibits endothelial serotonylation, leukocyte recruitment, and allergic inflammation. These data identify novel potential targets for intervention in allergy/asthma.AJP Lung Cellular and Molecular Physiology 07/2012; 303(8):L642-60. · 3.52 Impact Factor