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J Pharm Pharmacol. 2013 Aug;65(8):1204-13. doi: 10.1111/jphp.12087. Epub 2013 Jun 7.

Inhibitory effect of carbazolequinone derivatives on lipopolysaccharide and interferon-γ-induced nitric oxide production in mouse macrophage RAW264.7 cells.

Author information

1
Department of Analytical Neurobiology, Meijo University, Tempaku, Nagoya, Japan. tomiyasu@meijo-u.ac.jp

Abstract

OBJECTIVES:

The aim of this study was to examine the mechanism underlying the inhibitory effect of our synthesized carbazolequinone derivatives on nitric oxide (NO) production in activated macrophages.

METHODS:

Lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-stimulated RAW264.7 macrophages were treated with carbazolequinone derivatives. The NO and prostaglandin E2 (PGE2 ) levels in cell culture supernatants fractions were measured by Greiss and ELISA assay, respectively. The expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) was assessed by the real-time RT-PCR method. Nuclear factor kappa B (NF-κB) activation was detected by an NF-κB-dependent luciferase reporter assay.

KEY FINDINGS:

Our synthesized carbazolequinone derivatives (7-methoxy-2-methylcarbazole-1,4-quinone, 6-methoxy-2-methylcarbazole-1,4-quinone and 6-chloro-2-methylcarbazole-1,4-quinone) significantly inhibited LPS/IFN-γ-induced NO production and iNOS expression in RAW264.7 cells. They also inhibited the LPS/IFN-γ-mediated induction of COX-2 expression and PGE2 production. In addition, the LPS/IFN-γ-induced transcription activity of NF-κB was attenuated. Using the RAW264.7-tsAM5NE co-culture system, we found that these carbazolequinone derivatives protected neuronally differentiated tsAM5NE cells from NO-induced cell death by inhibiting the production of NO.

CONCLUSIONS:

These results suggest that the three carbazolequinone derivatives inhibit LPS/IFN-γ-induced NO production via iNOS and COX-2 downregulation due to NF-κB inhibition. Therefore, these three carbazolequinone derivatives may be useful for developing a new drug against NO-mediated neurodegenerative diseases.

KEYWORDS:

COX-2; carbazolequinone; iNOS; nitric oxide; prostaglandin E2; tsAM5NE cells

PMID:
23837588
DOI:
10.1111/jphp.12087
[Indexed for MEDLINE]

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