Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity

J Neurochem. 2006 Sep;98(5):1458-64. doi: 10.1111/j.1471-4159.2006.03982.x. Epub 2006 Jun 27.

Abstract

Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western / methods
  • Butadienes / pharmacology
  • Cell Count / methods
  • Cerebral Cortex / cytology
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Embryo, Mammalian
  • Enzyme Inhibitors
  • Fibrinolytic Agents / pharmacology*
  • Immunohistochemistry / methods
  • Mice
  • Morpholines / pharmacology
  • Neurons / drug effects*
  • Neuropeptides / pharmacology
  • Nitriles / pharmacology
  • Nuclear Proteins / pharmacology
  • Serpins / pharmacology
  • Serum / physiology*
  • Time Factors
  • Tissue Plasminogen Activator / administration & dosage*
  • Tissue Plasminogen Activator / metabolism

Substances

  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Fibrinolytic Agents
  • Morpholines
  • Neuropeptides
  • Nitriles
  • Nuclear Proteins
  • Serpins
  • U 0126
  • neuroserpin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Tissue Plasminogen Activator