TITLE:
Pharmacological evaluation of a novel enhydrazone ester (CEE-1) as a dual inhibitor of the release of pro-inflammatory cytokines and prostanoids from human monocytes
AUTHORS:
Charles I. Ezeamuzie, Hanan Zamil, Hawraa Al-Baghli, Ivan O. Edafiogho
KEYWORDS:
Enhydrazone Ester; Prostaglandin E2; Monocyte; Anti-Inflammatory; Tumor Necrosis Factor-Alpha; Cytokines
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.8B,
August
8,
2013
ABSTRACT: CEE-1 (ethyl
4-phenylhydrazinocyclohex-3-en-2-oxo-6-phenyl-1-oate)—a novel enhydrazone ester, was tested in vitro for anti-inflammatory activity
against the release of pro-inflammatory cytokine and prostanoid from
lipopolysaccharide-activated human monocytes or human monocytic cell line
(U937). The effects were compared with those of standard anti-inflammatory
drugs dexamethasone and indomethacin. CEE-1 potently and strongly inhibited
the release of both tumor necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE2). The concentrations producing 50% inhibition (IC50 values) were 2.0 μM and 2.4 μM for TNF-α and PGE2, respectively. At
30 μM, the drug achieved almost complete inhibition of both mediators. Dexamethasone
had similar effects but indomethacin inhibited only the PGE2 release, and although CEE-1 was less potent than these two drugs, it had comparable efficacy. The compound appeared to act, at least, in part by inhibiting the
up-regulation of the mRNA for TNF-α as well as that of the prostanoid-synthetic
enzyme, cyclo-oxygenase-2 (COX-2). However, like dexamethasone, but unlike
indomethacin, CEE-1 did not affect COX-2 enzyme function. Thus, the profile of
activity of CEE-1 is similar to that of steroids rather than the non-steroidal
anti-inflammatory drugs. Structure-activity study showed that the presence of a
simple aromatic ring attached via an NH-NH group was critical for activity. At
the concentrations that completely inhibited mediator release, the compound displayed
no significant in vitro toxicity on
the cells. These results show that CEE-1 is a dual inhibitor of the release of
cytokines and prostanoids, and therefore could be a potential alternative to
steroids in the treatment of inflammatory diseases.