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Mediators of Inflammation
Volume 2015, Article ID 510679, 9 pages
http://dx.doi.org/10.1155/2015/510679
Research Article

Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo

1Laboratory of Neuroplasticity and Neuroproteomics, KU Leuven, Naamsestraat 59, 3000 Leuven, Belgium
2Inflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, Belgium
3Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium
4Molecular Design and Synthesis, KU Leuven, Celestijnenlaan 200f, 3001 Leuven, Belgium
5Organic and Bio-Polymer Chemistry, UHasselt, Agoralaan Building D, 3590 Diepenbeek, Belgium
6Laboratory of Neural Circuit Development and Regeneration, KU Leuven, Naamsestraat 61, 3000 Leuven, Belgium

Received 18 May 2015; Accepted 2 July 2015

Academic Editor: Denis Girard

Copyright © 2015 J. Aerts et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A hydroxypyrone-based matrix metalloproteinase (MMP) inhibitor was synthesized and assayed for its inhibitory capacity towards a panel of ten different MMPs. The compound exhibited selective inhibition towards MMP-12. The effects of inhibition of MMP-12 on endotoxemia and inflammation-induced blood-cerebrospinal fluid barrier (BCSFB) disruption were assessed both in vitro and in vivo. Similar to MMP-12 deficient mice, inhibitor-treated mice displayed significantly lower lipopolysaccharide- (LPS-) induced lethality compared to vehicle treated controls. Following LPS injection Mmp-12 mRNA expression was massively upregulated in choroid plexus tissue and a concomitant increase in BCSFB permeability was observed, which was restricted in inhibitor-treated mice. Moreover, an LPS-induced decrease in tight junction permeability of primary choroid plexus epithelial cells was attenuated by inhibitor application in vitro. Taken together, this hydroxypyrone-based inhibitor is selective towards MMP-12 and displays anti-inflammatory activity in vitro and in vivo.