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Abstract #23825 Published in IGR 11-2
Antiglaucoma drug GLC756 and its effect on cellular cAMP and tumor necrosis factor alpha release in vitro of activated human monocytic leukemia cells
Laengle UW; Markstein R; Cazaubon C; Roman DJapanese Journal of Ophthalmology 2009; 53: 159-163
PURPOSE: GLC756, a putative antiglaucoma drug with dopamine D(2) agonist and D(1) antagonist properties, significantly decreases tumor necrosis factor alpha (TNF-alpha) levels in lipopolysaccharide (LPS)-induced rats. The present study describes the effects of GLC756 on cellular adenosine 3', 5'-cyclic monophosphate (cAMP) in relation to TNF-alpha production on LPS-stimulated human acute monocytic leukemia cells. METHODS: A human peripheral blood acute monocytic leukemia cell line (THP-1) was activated via LPS. THP-1 cells were incubated with GLC756 or betamethasone (positive control) at concentrations of 1, 10, and 30 microM. The TNF-alpha concentration in supernatant and cAMP levels in cellular extract were measured by enzyme-linked immunosorbent assay 0,1, 2.5, 4.5, 7, and 24 h post-activation. RESULTS: Compared with LPS controls, both GLC756 at 30 muM and betamethasone at ≥1 microM had a significant inhibitory effect on TNF-alpha release from THP-1 cells 2.5 to 24 h post-activation. Parallel to the TNF-alpha decrease, GLC756 induced significant increases of cellular cAMP 2.5 and 7 h post-activation. Betamethasone had no effect on the cellular cAMP level. CONCLUSION: Intracellular signaling pathway leading to inhibition of the production of the proinflammatory cytokine TNF-alpha after GLC756 treatment might be mediated through the second messenger cAMP.
Department of Toxicology & Pathology, Novartis Pharma AG, Basel, Switzerland. Ulrich.Laengle@novartis.com
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
3.6 Cellular biology (Part of: 3 Laboratory methods)