title: The anti-inflammatory activity of a novel fused-cyclopentenone phosphonate and its potential in the local treatment of experimental colitis.
abstract: A novel fused-cyclopentenone phosphonate compound, namely, diethyl 3-nonyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (P-5), was prepared and tested in vitro (LPS-activated macrophages) for its cytotoxicity and anti-inflammatory activity and in vivo (DNBS induced rat model) for its potential to ameliorate induced colitis. Specifically, the competence of P-5 to reduce TNFα, IL-6, INFγ, MCP-1, IL-1α, MIP-1α, and RANTES in LPS-activated macrophages was measured. Experimental colitis was quantified in the rat model, macroscopically and by measuring the activity of tissue MPO and iNOS and levels of TNFα and IL-1β. It was found that P-5 decreased the levels of TNFα and the tested proinflammatory cytokines and chemokines in LPS-activated macrophages. In the colitis-induced rat model, P-5 was effective locally in reducing mucosal inflammation. This activity was equal to the activity of local treatment with 5-aminosalicylic acid. It is speculated that P-5 may be used for the local treatment of IBD (e.g., with the aid of colon-specific drug platforms). Its mode of action involves inhibition of the phosphorylation of MAPK ERK but not of p38 and had no effect on IκBα.
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
authors.forename: Dorit
authors.identifier: 0000-0002-9979-8395
authors.initials: D
authors.lastname: Moradov
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
authors.forename: Helena
authors.initials: H
authors.lastname: Shifrin
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Harel
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
authors.forename: Mirela
authors.initials: M
authors.lastname: Nadler-Milbauer
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
authors.forename: Marta
authors.initials: M
authors.lastname: Weinstock
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
authors.forename: Morris
authors.initials: M
authors.lastname: Srebnik
authors.affiliation: Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel ; The Harvey M. Krueger Family Center for Nanoscience and Nanotechnology, The Hebrew University, 91904 Jerusalem, Israel ; The David R. Bloom Center of Pharmacy, The Hebrew University, 91120 Jerusalem, Israel.
authors.forename: Abraham
authors.identifier: 0000-0001-6212-3725
authors.initials: A
authors.lastname: Rubinstein