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

• Main Authors: J. Aerts (Author), R. E. Vandenbroucke (Author), R. Dera (Author), S. Balusu (Author), E. Van Wonterghem (Author), L. Moons (Author), C. Libert (Author), W. Dehaen (Author), L. Arckens (Author)
• Format: Book
• Published: Hindawi Limited, 2015-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 0962-9351; 1466-1861; 10.1155/2015/510679
• Keywords: Pathology; RB1-214
• Source: Mediators of Inflammation, Vol 2015 (2015)

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.