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Selective Inhibition of MMP-2 Does Not Alter Neurological Recovery after Spinal Cord Injury.
- Source :
-
ACS chemical neuroscience [ACS Chem Neurosci] 2016 Nov 16; Vol. 7 (11), pp. 1482-1487. Date of Electronic Publication: 2016 Aug 25. - Publication Year :
- 2016
-
Abstract
- Matrix metalloproteinase (MMP)-2 knockout (KO) mice show impaired neurological recovery after spinal cord injury (SCI), suggesting that this proteinase is critical to recovery processes. However, this finding in the KO has been confounded by a compensatory increase in MMP-9. We synthesized the thiirane mechanism-based inhibitor ND-378 and document that it is a potent (nanomolar) and selective slow-binding inhibitor of MMP-2 that does not inhibit the closely related MMP-9 and MMP-14. ND-378 crosses the blood-spinal cord barrier, achieving therapeutic concentrations in the injured spinal cord. Spinal-cord injured mice treated with ND-378 showed no change in long-term neurological outcomes, suggesting that MMP-2 is not a key determinant of locomotor recovery.
- Subjects :
- Animals
Disease Models, Animal
Drug Design
Drug Evaluation, Preclinical
Male
Matrix Metalloproteinase 14 metabolism
Matrix Metalloproteinase 2 genetics
Matrix Metalloproteinase 9 metabolism
Matrix Metalloproteinase Inhibitors chemical synthesis
Matrix Metalloproteinase Inhibitors pharmacokinetics
Mice
Mice, Knockout
Molecular Docking Simulation
Molecular Structure
Motor Activity drug effects
Motor Activity physiology
Phenyl Ethers chemical synthesis
Phenyl Ethers pharmacokinetics
Recovery of Function drug effects
Spinal Cord drug effects
Spinal Cord Injuries drug therapy
Sulfones chemical synthesis
Sulfones pharmacokinetics
Matrix Metalloproteinase 2 metabolism
Matrix Metalloproteinase Inhibitors pharmacology
Phenyl Ethers pharmacology
Recovery of Function physiology
Spinal Cord enzymology
Spinal Cord Injuries enzymology
Sulfones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1948-7193
- Volume :
- 7
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- ACS chemical neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 27551907
- Full Text :
- https://doi.org/10.1021/acschemneuro.6b00217