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Received for publication March 16, 2006.
Revised June 12, 2006.
Accepted for publication June 12, 2006.
Carbon monoxide-releasing molecules (CO-RMs) are emerging as a new class of pharmacological agents that regulate important cellular function by liberating CO in biological systems. Here, we examined the role of CORM-3 in modulating neuro-inflammatory responses in BV-2 microglial cells, considering its practical application as a novel therapeutic alternative in the treatment of stroke. BV-2 microglia cells were incubated for 24 h in normoxic conditions with thrombin alone or in combination with interferon-
to simulate the inflammatory response. Cells were also subjected to 12 h hypoxia and reoxygenated for 24 h in the presence of thrombin and IFN-. In both set of experiments, the anti-inflammatory action of CORM-3 was evaluated by assessing its effect on nitric oxide production (nitrite levels) and TNF-
release. CORM-3 (75 µM) did not show any cytotoxicity and markedly attenuated the inflammatory response to thrombin and interferon- in normoxia and to a lesser extent in hypoxia as evidenced by a significant reduction in nitrite and TNF- production. Inactive CORM-3, which does not liberate CO and is used as a negative control, failed to prevent the increase in inflammatory mediators. Blockade of endogenous CO production by tin protoporphyrin-IX did not change the anti-inflammatory activity of CORM-3 suggesting that CO liberated from the compound is responsible for the observed effects. In addition, inhibition of the mitogen-activated protein kinases PI3K and ERK amplified the anti-inflammatory effect of CORM-3. These results suggest that the anti-inflammatory activity of CORM-3 could be exploited to mitigate microglia activity in stroke and other neuro-inflammatory diseases.
Key words:
BV-2 microglia, carbon monoxide-releasing molecules, hypoxia-reoxygenation, inflammation, interferon-gamma, thrombin
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