title: Effect of GLC756, a novel mixed dopamine D1 receptor antagonist and dopamine D2 receptor agonist, on TNF-alpha release in vitro from activated rat mast cells.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is released from activated mast cells via an IgE-dependent mechanisms, and plays a crucial role in ocular allergic 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 IgE/anti-IgE. Rat mast cells were incubated with latanoprost, timolol, GLC756 or betamethasone (positive control) at concentrations of 0.1, 1, 10 and 30 microM. 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 microM, had no significant effect on TNF-alpha release from rat mast cells measured 5h after activation. By contrast, the dopaminergic drug GLC756 compared to controls in the concentration range 1-30 microM 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.
authors.affiliation: Department of Toxicology/Pathology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Ulrich Wilhelm
authors.initials: UW
authors.lastname: Laengle
authors.forename: Rudolf
authors.initials: R
authors.lastname: Markstein
authors.forename: Dominique
authors.initials: D
authors.lastname: Pralet
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seewald
authors.forename: Danielle
authors.initials: D
authors.lastname: Roman
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000077338:Latanoprost; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013999:Timolol / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D011461:Prostaglandins F, Synthetic; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C102871:SDZ GLC 756; D014409:Tumor Necrosis Factor-alpha; D000077338:Latanoprost; D013999:Timolol