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

Mediators of Inflammation
J AertsL Arckens

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.

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Citations

Nov 4, 2016·International Journal of Molecular Sciences·Inge Van HoveLieve Moons
Oct 27, 2017·American Journal of Physiology. Cell Physiology·Alexa N LauerChristian Schwerk
Apr 7, 2019·Molecular Diversity·Vesna Petrović PerokovićSrđanka Tomić
Jan 17, 2017·Molecular Neurobiology·Lucineia Gainski DanielskiFabrícia Petronilho

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Methods Mentioned

BETA
NMR
column chromatography
dissection

Software Mentioned

geNorm Housekeeping Gene ( HKG ) Selection
GraphPad Prism

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