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Role of matrix metalloproteinases in delayed cortical responses after stroke

Bing-Qiao Zhao1, Sophia Wang, Hahn-Young Kim

  • 1Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149-2401, Charlestown, Massachusetts 02129, USA.

Nature Medicine
|March 28, 2006
PubMed

Insights

Matrix metalloproteinases (MMPs) play a beneficial role in stroke recovery by promoting neurovascular remodeling. Inhibiting MMPs during delayed stroke phases worsens brain injury and impairs functional recovery.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Matrix metalloproteinases (MMPs) are enzymes involved in central nervous system (CNS) physiology and pathology.
  • MMPs are implicated in stroke, degrading the neurovascular matrix, causing blood-brain barrier injury, edema, and hemorrhage.
  • MMP inhibitors are explored for acute stroke therapy, but their role in delayed stroke phases is unclear.

Purpose of the Study:

  • To investigate the role of MMPs in delayed cortical responses following focal cerebral ischemia in rats.
  • To determine if MMPs contribute to beneficial plasticity and remodeling during stroke recovery.

Main Methods:

  • Induction of focal cerebral ischemia in rats.
  • Analysis of MMP-9 expression and its colocalization with neurovascular remodeling markers in the peri-infarct cortex at 7-14 days post-stroke.
  • Administration of MMP inhibitors at 7 days post-stroke and assessment of neurovascular remodeling, brain injury, and functional recovery at 14 days.
  • Evaluation of the involvement of vascular endothelial growth factor (VEGF) signaling.

Main Results:

  • MMP-9 was upregulated in the peri-infarct cortex 7-14 days after stroke, co-localizing with neurovascular remodeling markers.
  • Treatment with MMP inhibitors at 7 days post-stroke suppressed neurovascular remodeling, exacerbated ischemic brain injury, and impaired functional recovery at 14 days.
  • MMP inhibition reduced endogenous VEGF signaling, while exogenous VEGF administration ameliorated the negative effects of MMP inhibitors on infarction.

Conclusions:

  • MMPs play a crucial role in mediating beneficial neurovascular remodeling and functional recovery during delayed phases after stroke.
  • Targeting MMPs with inhibitors for acute stroke therapy may be detrimental for long-term recovery.
  • Strategies modulating MMP activity, rather than inhibition, may be beneficial for promoting stroke recovery.

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