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PMID: 12196576 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 17 ·2002-09-01 ·Pages 7526-35

Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z

Abstract

Inflammation in general and proteinases generated as a result are likely mediators of early secondary pathogenesis after spinal cord injury. We report that matrix metalloproteinase-9 (MMP-9) plays an important role in blood-spinal cord barrier dysfunction, inflammation, and locomotor recovery. MMP-9 was present in the meninges and neurons of the uninjured cord. MMP-9 increased rapidly after a moderate contusion spinal cord injury, reaching a maximum at 24 hr, becoming markedly reduced by 72 hr, and not detectable at 7 d after injury. It was seen in glia, macrophages, neutrophils, and vascular elements in the injured spinal cord at 24 hr after injury. The natural tissue inhibitors of MMPs were unchanged over this time course. MMP-9-null mice exhibited significantly less disruption of the blood-spinal cord barrier, attenuation of neutrophil infiltration, and significant locomotor recovery compared with wild-type mice. Similar findings were observed in mice treated with a hydroxamic acid MMP inhibitor from 3 hr to 3 d after injury, compared with the vehicle controls. Moreover, the area of residual white matter at the lesion epicenter was significantly greater in the inhibitor-treated group. This study provides evidence that MMP-9 plays a key role in abnormal vascular permeability and inflammation within the first 3 d after spinal cord injury, and that blockade of MMPs during this critical period attenuates these vascular events and leads to improved locomotor recovery. Our findings suggest that early inhibition of MMPs may be an efficacious strategy for the spinal cord-injured patient.

MeSH Terms
Animals Astrocytes/metabolism,pathology Blood Vessels/metabolism,pathology Capillary Permeability Disease Models, Animal Disease Progression Enzyme Activation/drug effects Enzyme Inhibitors/pharmacology Immunohistochemistry Macrophages/metabolism,pathology Male Matrix Metalloproteinase 9/deficiency,metabolism Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases/deficiency,metabolism Meninges/metabolism,pathology Mice Mice, Knockout Motor Activity/drug effects Motor Neurons/metabolism,pathology Neutrophil Infiltration/drug effects Recovery of Function/drug effects Spinal Cord/blood supply,pathology,physiopathology Spinal Cord Injuries/drug therapy,pathology,physiopathology
Chemicals
Enzyme Inhibitors Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases Matrix Metalloproteinase 9
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Noble Linda J
Department of Neurosurgery and Anatomy, University of California at San Francisco, San Francisco, California 94143-0520, USA.
Donovan Frances
Igarashi Takuji
Goussev Staci
Werb Zena
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2002-09-01
Pages
7526-35
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC2792199
Subset
IM
Grants
NINDS NIH HHS · R01 NS039278 · United States
NINDS NIH HHS · R01 NS039278-02 · United States
NINDS NIH HHS · R01 NS39278 · United States
External Links
PubMed source PMC Full Text View journal details
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