title: Selective Inhibition of MMP-2 Does Not Alter Neurological Recovery after Spinal Cord Injury.
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.
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Haoqian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Alpa
authors.initials: A
authors.lastname: Trivedi
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Mahasenan
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Noble-Haeusslein
authors.affiliation: Department of Chemistry and Biochemistry and ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.|Department of Neurological Surgery and Physical Therapy and ∥Rehabilitation Science, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology*; D013450:Sulfones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C507096:Mmp14 protein, mouse; C000620651:ND-378; D010647:Phenyl Ethers; D013450:Sulfones; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14
keywords: MMP-2; ND-378; brain distribution; spinal cord injury