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-...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2015/510679 |
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| author | J. Aerts R. E. Vandenbroucke R. Dera S. Balusu E. Van Wonterghem L. Moons C. Libert W. Dehaen L. Arckens |
| author_facet | J. Aerts R. E. Vandenbroucke R. Dera S. Balusu E. Van Wonterghem L. Moons C. Libert W. Dehaen L. Arckens |
| author_sort | J. Aerts |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2c5d8878ebf24e8887ea71d2c0b5d19f |
| institution | OA Journals |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-2c5d8878ebf24e8887ea71d2c0b5d19f2025-08-20T02:38:49ZengWileyMediators of Inflammation0962-93511466-18612015-01-01201510.1155/2015/510679510679Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In VivoJ. Aerts0R. E. Vandenbroucke1R. Dera2S. Balusu3E. Van Wonterghem4L. Moons5C. Libert6W. Dehaen7L. Arckens8Laboratory of Neuroplasticity and Neuroproteomics, KU Leuven, Naamsestraat 59, 3000 Leuven, BelgiumInflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, BelgiumMolecular Design and Synthesis, KU Leuven, Celestijnenlaan 200f, 3001 Leuven, BelgiumInflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, BelgiumInflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, BelgiumLaboratory of Neural Circuit Development and Regeneration, KU Leuven, Naamsestraat 61, 3000 Leuven, BelgiumInflammation Research Center, VIB, Technologiepark 927, 9052 Ghent, BelgiumMolecular Design and Synthesis, KU Leuven, Celestijnenlaan 200f, 3001 Leuven, BelgiumLaboratory of Neuroplasticity and Neuroproteomics, KU Leuven, Naamsestraat 59, 3000 Leuven, BelgiumA 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.http://dx.doi.org/10.1155/2015/510679 |
| spellingShingle | J. Aerts R. E. Vandenbroucke R. Dera S. Balusu E. Van Wonterghem L. Moons C. Libert W. Dehaen L. Arckens 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 |
| title | Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo |
| title_full | Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo |
| title_fullStr | Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo |
| title_full_unstemmed | Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo |
| title_short | Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo |
| title_sort | synthesis and validation of a hydroxypyrone based potent and specific matrix metalloproteinase 12 inhibitor with anti inflammatory activity in vitro and in vivo |
| url | http://dx.doi.org/10.1155/2015/510679 |
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