Effects of antiglaucoma drugs GLC756, a novel dopamine D2 agonist and D1 antagonist, and timolol on endotoxin-induced TNF-alpha release in serum of rats.
OBJECTIVE
Anti-inflammatory activity of an antiglaucoma drug may be an advantage for long-term treatment of glaucoma since it may reduce the risk of treatment-related inflammatory processes in outer compartments of the eye and probably also prevent or delay progression of glaucomatous retinal neurodegeneration. In this study, the effect of GLC756, a novel mixed dopamine D 2 receptor agonist and dopamine D 1 receptor antagonist, and timolol on endo-toxin-induced cytokine tumor necrosis factor-alpha (TNF-alpha) release in serum was examined.


METHODS
For endotoxin-induced TNF-alpha release, 8-week-old Lewis rats were intravenously injected with 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone were either systemically (1 mg/kg SC for 5 days) or topically (0.4%, 0.5%, and 0.1%, respectively, 20 microL eye drops given 16 times over 48 hours in left and right eye) administered. TNF-alpha was measured in serum 2 and 48 hours after LPS induction.


RESULTS
A marked TNF-alpha increase in serum was found 2 hours after LPS induction. Administration of GLC756 and betamethasone, systemically and topically, decreased TNF-alpha release. However, due to large scattering of mean values only the effect of systemically administered GLC756 was statistically significant. In contrast, timolol increased TNF-alpha values stronger than LPS alone.


CONCLUSIONS
The significant suppression of LPS-induced TNF-alpha increase by GLC756 suggests an additional anti-inflammatory potential of the dopaminergic compound in the treatment of glaucoma.
Laengle
U W
UW
Department of Toxicology/Pathology, Novartis Pharma AG, Basel--Switzerland. Ulrich.Laengle@novartis.com
Markstein
R
R
Schneider
V
V
Roman
D
D
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000959:Antihypertensive Agents; D001623:Betamethasone / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity*; D009883:Ophthalmic Solutions / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D012486:Salmonella typhimurium; D013999:Timolol / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D008070:Lipopolysaccharides; D009883:Ophthalmic Solutions; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C102871:SDZ GLC 756; D014409:Tumor Necrosis Factor-alpha; D013999:Timolol; D001623:Betamethasone