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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
pharmacology, toxicology and pharmaceutics
Diclofenac enhances proinflammatory cytokine-induced nitric oxide production through NF-κB signaling in cultured astrocytes
Toxicology and Applied Pharmacology, Volume 238, No. 1, Year 2009
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Description
Recently, the number of reports of encephalitis/encephalopathy associated with influenza virus has increased. In addition, the use of a non-steroidal anti-inflammatory drug, diclofenac sodium (DCF), is associated with a significant increase in the mortality rate of influenza-associated encephalopathy. Activated astrocytes are a source of nitric oxide (NO), which is largely produced by inducible NO synthase (iNOS) in response to proinflammatory cytokines. Therefore, we investigated whether DCF enhances nitric oxide production in astrocytes stimulated with proinflammatory cytokines. We stimulated cultured rat astrocytes with three cytokines, interleukin-1β, tumor necrosis factor-α and interferon-γ, and then treated the astrocytes with DCF or acetaminophen (N-acetyl-p-aminophenol: APAP). iNOS and NO production in astrocyte cultures were induced by proinflammatory cytokines. The addition of DCF augmented NO production, but the addition of APAP did not. NF-κB inhibitors SN50 and MG132 inhibited iNOS gene expression in cytokine-stimulated astrocytes with or without DCF. Similarly, NF-κB p65 Stealth small interfering RNA suppressed iNOS gene expression in cytokine-stimulated astrocytes with or without DCF. LDH activity and DAPI staining showed that DCF induces cell damage in cytokine-stimulated astrocytes. An iNOS inhibitor, l-NMMA, inhibited the cytokine- and DCF-induced cell damage. In conclusion, this study demonstrates that iNOS and NO are induced in astrocyte cultures by proinflammatory cytokines. Addition of DCF further augments NO production. This effect is mediated via NF-κB signaling and leads to cell damage. The enhancement of DCF on NO production may explain the significant increase in the mortality rate of influenza-associated encephalopathy in patients treated with DCF. © 2009 Elsevier Inc. All rights reserved.
Authors & Co-Authors
Kakita, Hiroki
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Japan, Kasugai
Aichi Developmental Disability Center
Aoyama, Mineyoshi
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Hussein, Mohamed
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Egypt, Giza
Cairo University
Egypt, Giza
Vacsera
Kato, Shin
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Suzuki, Satoshi
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Ito, Tetsuya
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Togari, Hajime
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Asai, Kiyofumi
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Statistics
Citations: 17
Authors: 8
Affiliations: 4
Identifiers
Doi:
10.1016/j.taap.2009.04.014
ISSN:
0041008X
e-ISSN:
10960333
Research Areas
Cancer
Genetics And Genomics