Selective Inhibition of MMP-2 Does Not Alter Neurological Recovery after Spinal Cord Injury

Ming Gao; Haoqian Zhang; Alpa Trivedi; Kiran V. Mahasenan; Valerie A. Schroeder; William R. Wolter; Mark A. Suckow; Shahriar Mobashery; Linda J. Noble-Haeusslein; Mayland Chang

doi:10.1021/acschemneuro.6b00217

Selective Inhibition of MMP-2 Does Not Alter Neurological Recovery after Spinal Cord Injury

Ming Gao, Haoqian Zhang, Alpa Trivedi, Kiran V. Mahasenan, Valerie A. Schroeder, William R. Wolter, Mark A. Suckow, Shahriar Mobashery, Linda J. Noble-Haeusslein, Mayland Chang

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English
Pages (from-to)	1482-1487
Number of pages	6
Journal	ACS Chemical Neuroscience
Volume	7
Issue number	11
DOIs	https://doi.org/10.1021/acschemneuro.6b00217
State	Published - Nov 16 2016

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

Keywords

MMP-2
ND-378
brain distribution
spinal cord injury

ASJC Scopus subject areas

Biochemistry
Physiology
Cognitive Neuroscience
Cell Biology

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10.1021/acschemneuro.6b00217

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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.",

keywords = "MMP-2, ND-378, brain distribution, spinal cord injury",

author = "Ming Gao and Haoqian Zhang and Alpa Trivedi and Mahasenan, {Kiran V.} and Schroeder, {Valerie A.} and Wolter, {William R.} and Suckow, {Mark A.} and Shahriar Mobashery and Noble-Haeusslein, {Linda J.} and Mayland Chang",

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doi = "10.1021/acschemneuro.6b00217",

language = "English",

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AU - Gao, Ming

AU - Zhang, Haoqian

AU - Trivedi, Alpa

AU - Mahasenan, Kiran V.

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Suckow, Mark A.

AU - Mobashery, Shahriar

AU - Noble-Haeusslein, Linda J.

AU - Chang, Mayland

PY - 2016/11/16

Y1 - 2016/11/16

N2 - 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.

AB - 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.

KW - MMP-2

KW - ND-378

KW - brain distribution

KW - spinal cord injury

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Selective Inhibition of MMP-2 Does Not Alter Neurological Recovery after Spinal Cord Injury

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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