A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia.
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.
Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California 92037, USA.
Zezong
Z
Gu
Jiankun
J
Cui
Stephen
S
Brown
Rafael
R
Fridman
Shahriar
S
Mobashery
Alex Y
AY
Strongin
Stuart A
SA
Lipton
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002544:Cerebral Infarction / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017364:Collagenases / Q000494:pharmacology; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004792:Enzyme Precursors / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015918:Infusion Pumps, Implantable; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D007700:Kinetics; D007797:Laminin / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000494:pharmacology / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000494:pharmacology; D053504:Matrix Metalloproteinases, Membrane-Associated; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015424:Reperfusion; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D004792:Enzyme Precursors; D006573:Heterocyclic Compounds, 1-Ring; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D017364:Collagenases; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; C120487:pro-matrix metalloproteinase 9; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9