Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo.
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.
Laboratory of Neuroplasticity and Neuroproteomics, KU Leuven, Naamsestraat 59, 3000 Leuven, Belgium.
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J
Aerts
Inflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.
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RE
Vandenbroucke
Molecular Design and Synthesis, KU Leuven, Celestijnenlaan 200f, 3001 Leuven, Belgium ; Organic and Bio-Polymer Chemistry, UHasselt, Agoralaan Building D, 3590 Diepenbeek, Belgium.
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R
Dera
Inflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.
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S
Balusu
Inflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.
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Van Wonterghem
Laboratory of Neural Circuit Development and Regeneration, KU Leuven, Naamsestraat 61, 3000 Leuven, Belgium.
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L
Moons
Inflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.
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C
Libert
Molecular Design and Synthesis, KU Leuven, Celestijnenlaan 200f, 3001 Leuven, Belgium.
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W
Dehaen
Laboratory of Neuroplasticity and Neuroproteomics, KU Leuven, Naamsestraat 59, 3000 Leuven, Belgium.
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L
Arckens
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019446:Endotoxemia; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12