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Title: | Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo | Authors: | Aerts, J. Vandenbroucke, R. E. DERA, Rafael Balusu, S. Van Wonterghem, E. Moons, L. Libert, C. Dehaen, W. Arckens, L. |
Issue Date: | 2015 | Publisher: | HINDAWI PUBLISHING CORP | Source: | MEDIATORS OF INFLAMMATION, 2015, (Art N° 510679) | 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. | Notes: | [Aerts, J.; Arckens, L.] Katholieke Univ Leuven, Lab Neuroplast & Neuroprote, B-3000 Leuven, Belgium. [Vandenbroucke, R. E.; Balusu, S.; Van Wonterghem, E.; Libert, C.] VIB, Inflammat Res Ctr, B-9052 Ghent, Belgium. [Vandenbroucke, R. E.; Balusu, S.; Van Wonterghem, E.; Libert, C.] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium. [Dera, R.; Dehaen, W.] Katholieke Univ Leuven, Mol Design & Synth, B-3000 Leuven, Belgium. [Dera, R.] UHasselt, Organ & Biopolymer Chem, B-3590 Diepenbeek, Belgium. [Moons, L.] Katholieke Univ Leuven, Lab Neural Circuit Dev & Regenerat, B-3000 Leuven, Belgium. | Document URI: | http://hdl.handle.net/1942/22486 | ISSN: | 0962-9351 | e-ISSN: | 1466-1861 | DOI: | 10.1155/2015/510679 | ISI #: | 000360123200001 | Rights: | 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. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2016 |
Appears in Collections: | Research publications |
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510679.pdf | Published version | 1.73 MB | Adobe PDF | View/Open |
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