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Intranuclear matrix metalloproteinases promote DNA damage and apoptosis induced by oxygen-glucose deprivation in

J W Hill1, R Poddar, J F Thompson

  • 1University of New Mexico Health Sciences Center, Department of Neurology, Albuquerque, NM 87131, USA.

Neuroscience
|June 20, 2012
PubMed

Insights

Intranuclear matrix metalloproteinase (MMP) activity degrades DNA repair proteins, causing neuronal death after stroke. Inhibiting MMP-2 and MMP-9 reduces this damage and promotes neuron survival, revealing a novel intrinsic apoptotic pathway.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Elevated extracellular matrix metalloproteinase (MMP) activity contributes to blood-brain barrier disruption and neuronal death post-ischemia/reperfusion.
  • Previous research indicated intranuclear MMP-2 and MMP-9 (gelatinase) activity degrades DNA repair proteins and increases oxidative DNA damage in neurons after ischemic stroke.

Purpose of the Study:

  • To investigate the role of intranuclear MMP-2 and MMP-9 activity in neuronal apoptosis following ischemic stroke.
  • To confirm and extend in vivo findings using an in vitro oxygen-glucose deprivation (OGD) model.

Main Methods:

  • In vivo middle cerebral artery occlusion (MCAO) model in rats treated with a broad-spectrum MMP inhibitor.
  • In vitro oxygen-glucose deprivation (OGD) model using primary cortical neurons.
  • Measurement of intranuclear and extracellular gelatinase activity, levels of DNA repair proteins (PARP1, XRCC1, OGG1), and oxidative DNA damage.

Main Results:

  • In vivo MMP inhibition significantly reduced neuronal apoptosis after MCAO.
  • In vitro OGD induced increased intranuclear gelatinase activity, primarily MMP-2, with unchanged extracellular levels.
  • Intranuclear gelatinase activity correlated with decreased DNA repair proteins and PARP1 activity, increased oxidative DNA damage, and reduced neuronal survival; inhibition of MMP-2/9 improved these outcomes.

Conclusions:

  • Intranuclear MMP-2 and MMP-9 activity plays a novel, intrinsic role in neuronal apoptosis during acute ischemic stroke.
  • Targeting intranuclear gelatinase activity represents a potential therapeutic strategy for stroke injury.

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