Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94

J Cereb Blood Flow Metab. 2000 Dec;20(12):1681-9. doi: 10.1097/00004647-200012000-00007.


It has been shown recently that matrix metalloproteinases (MMPs) are elevated after cerebral ischemia. In the current study, we investigated the pathophysiologic role for MMP-9 (gelatinase B, EC. in a mouse model of permanent focal cerebral ischemia, using a combination of genetic and pharmacologic approaches. Zymography and Western blot analysis demonstrated that MMP-9 protein levels were rapidly up-regulated in brain after ischemic onset. Reverse transcription polymerase chain reaction showed increased transcription of MMP-9. There were no differences in systemic hemodynamic parameters and gross cerebrovascular anatomy between wild type mice and mutant mice with a targeted knockout of the MMP-9 gene. After induction of focal ischemia, similar reductions in cerebral blood flow were obtained. In the MMP-9 knockout mice, ischemic lesion volumes were significantly reduced compared with wild type littermates in male and female mice. In normal wild type mice, the broad spectrum MMP inhibitor BB-94 (batimastat) also significantly reduced ischemic lesion size. However, BB-94 had no detectable protective effect when administered to MMP-9 knockout mice subjected to focal cerebral ischemia. These data demonstrate that MMP-9 plays a deleterious role in the development of brain injury after focal ischemia.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / enzymology
  • Brain Ischemia / drug therapy
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Male
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Neuroprotective Agents / pharmacology
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology*
  • Protease Inhibitors / pharmacology*
  • Stroke / drug therapy
  • Stroke / metabolism
  • Stroke / pathology
  • Thiophenes / pharmacology*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology


  • Matrix Metalloproteinase Inhibitors
  • Neuroprotective Agents
  • Protease Inhibitors
  • Thiophenes
  • Phenylalanine
  • batimastat
  • Matrix Metalloproteinase 9