Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/175
Title: The Effect of a Novel Enaminone Derivative (CEE-1) on the Release of Pro-inflammatory Prostanoids from Human Monocytes
Authors: Hawraa Abbas Al-Baghli 
Supervisor: Prof. Charles I. Ezeamuzie
Keywords: Chronic inflammation;anti-inflammatory effects of CEE-1;pro-inflammatory prostanoids;Human monocytic cell line
Issue Date: 2011
Publisher:  Kuwait university - college of graduate studies
Abstract: Chronic inflammation is the major cause or component of most diseases including arthritis, asthma, inflammatory bowel disease, cancer and diabetes that afflict many people worldwide. Despite the dramatic development of anti-inflammatory treatments in the last few decades, treatment of inflammatory diseases has remained unsatisfactory, as the available drugs have low efficacy and serious adverse effects. This study investigated the anti-inflammatory effects of CEE-1, a novel enaminone derivative. The aim was to characterize the in vitro effect of the compound on the release of pro-inflammatory prostanoids (PGE2 and TXA2) and to compare it with its effect on cytokines release (TNFα). In addition, the mechanisms of action of CEE-1 were investigated. Human monocytic cell line (U-937) was used. The cells were cultured according to standard procedures and pre-treated with CEE-1 or appropriate controls for 30 min before they were stimulated with a combination of phorbol myristate acetate (PMA) and bacterial lipopolysaccharide (LPS). The inflammatory mediators released (PGE2, TXA2 and TNF-α) after 24 h were determined by ELISA. The expression of mRNA for cyclooxygenase enzyme (COX) was determined by Real-time PCR, while COX protein expression was determined by the Western blot technique. Results showed that CEE-1 is an effective inhibitor of prostanoid release. The concentration producing 50% inhibition of release of PGE2 (IC50 value) was 2.0 ± 0.3 μM, and at 30 μM, PGE2 release was almost completely abolished. The effect was comparable to that on TNF-α release. Comparison showed that dexamethasone also inhibited the release of both prostanoids and TNF-α, whereas indomethacin inhibited only v the prostanoids. The mechanism of the inhibitory effect of CEE-1 on prostanoid release appears to involve the inhibition of COX-2 gene transcription and protein expression. Blocking of COX enzyme functions, however, does not seem to be involved in the CEE-1 mechanism of action. Nevertheless, the fact that higher concentrations of CEE-1 were required for the inhibition of COX-2 mRNA expression than for the inhibition of prostanoid release suggests that additional mechanism(s) may also be involved. These results are the first to show an enaminone with dual cytokine and prostanoid inhibitory activities. This profile of activity, which is similar to that of steroids, rather than NSAIDs, makes CEE-1 a very promising potential anti-inflammatory agent that will have advantages over NSAIDs and be a possible alternative to steroids, in the treatment of inflammatory diseases.
URI: http://hdl.handle.net/123456789/175
Appears in Programs:0550 Pharmacology (M.Sc.)

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