Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 27, Pages 6401-6408Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1563-05.2005
Keywords
matrix metalloproteinases; thiirane inhibitor; laminin; proteolysis; neurons; apoptosis
Categories
Funding
- NCI NIH HHS [CA100475, R01 CA077470, CA77470, R01 CA100475] Funding Source: Medline
- NEI NIH HHS [EY09024, EY05477, R01 EY009024] Funding Source: Medline
- NICHD NIH HHS [P01 HD029587, HD29587] Funding Source: Medline
- NINDS NIH HHS [NS44326, R01 NS044326] Funding Source: Medline
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Neuronal cell death occurs during many neurodegenerative disorders and stroke. The aberrant, excessive activity of matrix metalloproteinases (MMPs), especially MMP-9, contributes directly to neuron apoptosis and brain damage (Rosenberg et al., 1996; Asahi et al., 2001; Gu et al., 2002; Horstmann et al., 2003). We determined that MMP-9 degrades the extracellular matrix protein laminin and that this degradation induces neuronal apoptosis in a transient focal cerebral ischemia model in mice. We also determined that the highly specific thiirane gelatinase inhibitor SB-3CT blocks MMP-9 activity, including MMP-9-mediated laminin cleavage, thus rescuing neurons from apoptosis. We conclude that MMP-9 is a highly promising drug target and that SB-3CT derivatives have significant therapeutic potential in stroke patients.
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