Effect of GLC756, a novel mixed dopamine D1 receptor antagonist an dopamine D2 receptor agonist, on TNF-alpha release in vitro from activated rat mast cells

Tumor necrosis factor-alpha (TNF-alpha) is released from activated mast cells via an IgE-dependent mechanisms, and plays a crucial role in ocular aller-ic inflammation. This study examined the influence of three antiglaucoma drugs differing in their chemical structure and pharmacological profile (i.e. latanoprost, timolol, GLC756) on TNF-alpha release from activated rat mast cells. A rat basophilic leukemia mast cell line (RBL-2H3) was activated via I-E/anti-IgE. Rat mast cells were incubated with latanoprost, timolol, GLC756 or betamethasone (positive control) at concentrations of 0.1, 1, 10 and 30 mu M. TNF-alpha concentration in supernatant was measured by ELISA 5 h post-activation. Compared to controls, the prostaglandin derivative latanoprost and the beta-blocker timolol in the concentration range 0.1-30 mu M, had no significant effect on TNF-alpha release from rat mast cells measured 5 h after activation. By contrast, the cloparninergic drug GLC756 compared to controls in the concentration range 1-30 mu M significantly inhibited TNF-alpha release from activated rat mast cells in a concentration-dependent manner. The positive control betamethasone inhibited TNF-alpha release almost completely at all concentrations tested. In conclusion, the results of this study suggest that latanoprost and timolol do not reduce inflammation triggered by activated mast cells. By contrast, the dopaminergic drug GLC756 inhibited TNF-alpha release from activated mast cells, suggesting an palliative potential of dopaminergic compounds on allergic conjunctivitis in topical glaucoma medication. (c) 2006 Elsevier Ltd. All rights reserved.