TY - JOUR
T1 - Selective Inhibition of MMP-2 Does Not Alter Neurological Recovery after Spinal Cord Injury
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
N1 - Publisher Copyright:
© 2016 American Chemical Society.
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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U2 - 10.1021/acschemneuro.6b00217
DO - 10.1021/acschemneuro.6b00217
M3 - Article
C2 - 27551907
AN - SCOPUS:84996602498
VL - 7
SP - 1482
EP - 1487
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 11
ER -