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Synthesis and validation of a hydroxypyrone-based, potent, and specific matrix metalloproteinase-12 inhibitor with anti-inflammatory activity in vitro and in vivo

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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.
Keywords
ENDOTOXIN, CLEAVAGE, SEPSIS, CANCER-THERAPY, INFLAMMATION, STROMELYSIN-1

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Chicago
Aerts, J, Roosmarijn Vandenbroucke, R Dera, Sriram Balusu, Elien Van Wonterghem, L Moons, Claude Libert, W Dehaen, and L Arckens. 2015. “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.
APA
Aerts, J, Vandenbroucke, R., Dera, R., Balusu, S., Van Wonterghem, E., Moons, L., Libert, C., et al. (2015). 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.
Vancouver
1.
Aerts J, Vandenbroucke R, Dera R, Balusu S, Van Wonterghem E, Moons L, et al. 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. 2015;
MLA
Aerts, J, Roosmarijn Vandenbroucke, R Dera, et al. “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 (2015): n. pag. Print.
@article{6971924,
  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.},
  articleno    = {510679},
  author       = {Aerts, J and Vandenbroucke, Roosmarijn and Dera, R and Balusu, Sriram and Van Wonterghem, Elien and Moons, L and Libert, Claude and Dehaen, W and Arckens, L},
  issn         = {0962-9351},
  journal      = {MEDIATORS OF INFLAMMATION},
  language     = {eng},
  pages        = {9},
  title        = {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},
  year         = {2015},
}

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