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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3

Mohamed G. Bani-Hani, David Greenstein, Brian E. Mann, Colin J. Green and Roberto Motterlini
Journal of Pharmacology and Experimental Therapeutics September 2006, 318 (3) 1315-1322; DOI: https://doi.org/10.1124/jpet.106.104729
Mohamed G. Bani-Hani
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David Greenstein
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Brian E. Mann
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Colin J. Green
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Roberto Motterlini
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Abstract

Carbon monoxide-releasing molecules 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 carbon monoxide-releasing molecule 3 (CORM-3) in modulating neuroinflammatory 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-γ to simulate the inflammatory response. Cells were also subjected to 12 h of hypoxia and reoxygenated for 24 h in the presence of thrombin and interferon-γ. 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 tumor necrosis factor (TNF)-α release. CORM-3 (75 μM) did not show any cytotoxicity and markedly attenuated the inflammatory response to thrombin and interferon-γ in normoxia and to a lesser extent in hypoxia as evidenced by a reduction in nitrite levels and TNF-α 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 phosphatidyl inositol 3 kinase and extracellular signal-regulated kinase 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 neuroinflammatory diseases.

Footnotes

  • doi:10.1124/jpet.106.104729.

  • ABBREVIATIONS: iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; HO, heme oxygenase; CO-RM, carbon monoxide-releasing molecule; CORM-3, tricarbonylchloro(lglycinato)ruthenium (II); SP600125, 1,9-pyrazoloanthrone; iCORM-3, inactivated CORM-3; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; PD98059, 2′-amino-3′-methoxyflavone; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; TNF, tumor necrosis factor; LDH, lactate dehydrogenase; IFN-γ, interferon-γ; SnPPIX, tin protoporphyrin-IX; MAPK, mitogen-activated protein kinase; PI3K, phosphatidyl inositol 3 kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; Thr, thrombin.

    • Received March 16, 2006.
    • Accepted June 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3

Mohamed G. Bani-Hani, David Greenstein, Brian E. Mann, Colin J. Green and Roberto Motterlini
Journal of Pharmacology and Experimental Therapeutics September 1, 2006, 318 (3) 1315-1322; DOI: https://doi.org/10.1124/jpet.106.104729

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3

Mohamed G. Bani-Hani, David Greenstein, Brian E. Mann, Colin J. Green and Roberto Motterlini
Journal of Pharmacology and Experimental Therapeutics September 1, 2006, 318 (3) 1315-1322; DOI: https://doi.org/10.1124/jpet.106.104729
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