1. A carbon monoxide-releasing molecule (CORM-3) attenuates lipopolysaccharide- and interferon-gamma-induced inflammation in microglia.
- Author
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Bani-Hani MG, Greenstein D, Mann BE, Green CJ, and Motterlini R
- Subjects
- Animals, Carbon Monoxide metabolism, Cell Line, Cell Survival, Enzyme Activation, Guanylate Cyclase metabolism, Heme Oxygenase (Decyclizing) metabolism, Inflammation metabolism, Microglia cytology, Microglia drug effects, Mitogen-Activated Protein Kinases antagonists & inhibitors, Nitric Oxide Synthase antagonists & inhibitors, Nitrites metabolism, Organometallic Compounds metabolism, Phosphoinositide-3 Kinase Inhibitors, Tumor Necrosis Factor-alpha metabolism, Carbon Monoxide physiology, Interferon-gamma pharmacology, Lipopolysaccharides pharmacology, Microglia metabolism, Organometallic Compounds pharmacology
- Abstract
The development of carbon monoxide-releasing molecules (CO-RMs) in recent years helped to shed more light on the diverse range of anti-inflammatory and cytoprotective activities of CO gas. In this study, we examined the effect of a ruthenium-based water-soluble CO carrier (CORM-3) on lipopolysaccharide (LPS)- and interferon-gamma (INF-gamma)-induced inflammatory responses in BV-2 microglial cells and explored the possible mechanisms of action. BV-2 microglial cells were stimulated with either LPS or INF-gamma in the presence of CORM-3 and the inflammatory response evaluated by assessing the effect on nitric oxide production (nitrite levels) and tumor necrosis factor-alpha (TNF-alpha) release. Similar experiments were also performed in the presence of inhibitors of guanylate cyclase (ODQ), NO synthase (L-NAME), heme oxygenase activity (tin protoporphyrin IX) or various mitogen-activated protein kinase (MAPK) inhibitors. CORM-3 significantly attenuated the inflammatory response to LPS and INF-gamma as evidenced by a significant reduction (p < 0.001) in nitrite levels and TNF-alpha production (P < 0.05). Such effect was maintained in the presence of ODQ, L-NAME or tin protoporphyrin without showing any cytotoxicity. The use of an inactive form of CORM-3 that does not contain carbonyl groups (Ru(DMSO)(4)Cl(2) failed to inhibit the increase in inflammatory markers suggesting that liberated CO mediates the observed effects. In addition, inhibition of phosphatidylinositol-3-phosphate kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways seemed to amplify the anti-inflammatory effect of CORM-3, particularly in cells stimulated with INF-gamma. These results suggest that the anti-inflammatory action of CORM-3 could be exploited to mitigate microglia activation in neuro-inflammatory diseases.
- Published
- 2006