Effects of antiglaucoma drugs timolol and GLC756, a novel dopamine D2 agonist and D1 antagonist, on endotoxin-induced-uveitis in rats.
Antiglaucoma drugs with anti-inflammatory properties may be of particular value for the long-term treatment of glaucoma since they may reduce the risk for treatment-related inflammatory processes in outer compartments of the eye. The purpose of this study was, to evaluate the effect of systemic and topical administration of GLC756, a novel mixed dopamine D(2) receptor agonist and D(1) receptor antagonist which lowered intraocular pressure in man, and timolol on endotoxin-induced-uveitis (EIU) in rats. For EIU, 8-week-old Lewis rats received an intravenous injection of 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone, as positive control, were administered either topically (0.4, 0.5, and 0.1%, respectively, 16-times 20 microl eye drops during 48 hr) or systemically (1 mg kg(-1) subcutaneously for 5 days). Protein content, released TNF-alpha, the number of cells as well as cells expressing TNF-alpha were determined in aqueous humor 48 hr after LPS-injection and served as parameters for inflammation. LPS induced an increase of protein content, infiltrating cells and cells expressing TNF-alpha in the aqueous humor. Topical and systemic administration of GLC756 and betamethasone, almost completely suppressed the increase of protein content and betamethasone in addition also suppressed the number of cells in aqueous humor. In conclusion, the almost complete suppression of LPS-induced protein increase in aqueous humor by GLC756 suggests an additional anti-inflammatory potential of dopaminergic compounds in glaucoma treatment. Timolol did not show any effect on EIU in rats.
Laengle
Ulrich Wilhelm
UW
Department of Toxicology/Pathology, Novartis Pharma AG, 4002-Basel, Switzerland. ulrich.laengle@pharma.novartis.com
Markstein
Rudolf
R
Schneider
Verena
V
Greiner
Brigitte
B
Roman
Danielle
D
D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001082:Aqueous Humor / Q000166:cytology / Q000378:metabolism; D001623:Betamethasone / Q000008:administration & dosage; D015259:Dopamine Agents / Q000008:administration & dosage*; D005136:Eye Proteins / Q000032:analysis; D005901:Glaucoma / Q000188:drug therapy; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides; D011804:Quinolines / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D013999:Timolol / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014605:Uveitis / Q000188:drug therapy*
D000319:Adrenergic beta-Antagonists; D000893:Anti-Inflammatory Agents; D015259:Dopamine Agents; D005136:Eye Proteins; D008070:Lipopolysaccharides; D011804:Quinolines; C102871:SDZ GLC 756; D014409:Tumor Necrosis Factor-alpha; D013999:Timolol; D001623:Betamethasone