Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury.
Matrix metalloproteinase-9 (MMP-9) activation plays an important role in blood-brain barrier (BBB) dysfunction after central nervous system injury. Oxidative stress is also implicated in the pathogenesis after cerebral ischemia and spinal cord injury (SCI), but the relationship between MMP-9 activation and oxidative stress after SCI has not yet been clarified. We examined MMP-9 expression after SCI using copper/zinc-superoxide dismutase (SOD1) transgenic (Tg) rats. Our results show that MMP-9 activity significantly increased after SCI in both SOD1 Tg rats and their wild-type (Wt) littermates, although the increase was less in the SOD1 Tg rats. This pattern of MMP-9 expression was further confirmed by immunostaining and Western blot analysis. In situ zymography showed that gelatinolytic activity increased after SCI in the Wt rats, while the increase was less in the Tg rats. Evans blue extravasation increased in both the Wt and Tg rats, but was less in the SOD1 Tg rats. Inhibitor studies showed that, with an intrathecal injection of SB-3CT (a selective MMP-2/MMP-9 inhibitor), the MMP activity, Evans blue extravasation, and apoptotic cell death decreased after SCI. We conclude that increased oxidative stress after SCI leads to MMP-9 upregulation, BBB disruption, and apoptosis, and that overexpression of SOD1 in Tg rats decreases oxidative stress and further attenuates MMP-9 mediated BBB disruption.
Yu
Fengshan
F
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
Kamada
Hiroshi
H
Niizuma
Kuniyasu
K
Endo
Hidenori
H
Chan
Pak H
PH
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005070:Evans Blue / Q000493:pharmacokinetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008833:Microcirculation / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000098:blood supply / Q000201:enzymology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation / Q000235:genetics
D004791:Enzyme Inhibitors; C000606290:SOD1 protein, human; D005070:Evans Blue; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020780:Matrix Metalloproteinase 9