Effects of latanoprost, timolol and GLC756, a novel dopamine D-2 agonist and D-1 antagonist on LTC4 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: INTRODUCTION: Glaucoma is a disease of the eye in which the optic nerve and retinal ganglion cells (RGCs) are injured, leading to the loss of the peripheral visual field and eventually to profound vision loss and blindness. Glaucoma is usually characterized by an increase in intraocular pressure (IOP), which is treated with ocular hypotensive drugs. However, both RGC apoptosis and optic nerve atrophy, due to glaucoma, can occur independently of IOP. AREAS COVERED: This review discusses several current and emerging treatments for glaucoma. Current research is updating the known properties of a number of drugs now used to treat glaucoma. Some drugs may offer neuroprotection, not only reducing vision loss, but restoring injured or compromised RGCs and optic nerve cells. Several molecules now under development aim to lower IOP primarily by enhancing aqueous drainage through conventional pathways of the trabecular meshwork and Schlemm's canal. Gene transfer models are being investigated, and a murine-derived neurotrophic growth factor (NGF) seems to offer the promise of actually restoring visual function in some patients. Drugs that are already widely used are being re-branded in preservative-free formulations. EXPERT OPINION: The ultimate goal in glaucoma research is to find new compounds that will not only normalize IOP, but also arrest or even reverse apoptotic damage to the optic nerve and RGCs to slow the rate of progression of the disease so that it will not interfere with the patient's ability to see and his/her quality of life. This should be obtained with affordable costs, minimal side effects and a reasonable schedule.Expert Opinion on Emerging Drugs 03/2011; 16(2):293-307. DOI:10.1517/14728214.2011.563733 · 3.06 Impact Factor
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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. DOI:10.1152/ajplung.00406.2011 · 4.08 Impact Factor