Role of tissue-derived plasminogen activator (t-PA) in an excitotoxic mouse model of neonatal white matter lesions

J Neuropathol Exp Neurol. 2004 Jan;63(1):53-63. doi: 10.1093/jnen/63.1.53.


White matter (WM) lesions in preterm newborns may lead to cerebral palsy. To study WM lesions in a mouse model, we used intrapallial stereotactic injections of ibotenic acid, an N-methyl-D-aspartate receptor agonist. Previous studies support a contribution of tissue-type plasminogen activator (t-PA) to the brain lesions seen in various adult excitotoxic models. Therefore, we studied both 5-day-old (P5) wild-type mice and t-PA knock-out (t-PA-/-) mice. The ibotenic acid doses required to induce WM cysts were lower in the wild-type mice (EC50 < 0.01 microg/animal) than in the t-PA-/- mice (EC50 = 2.5 microg/animal) (p < 0.01), indicating the existence of t-PA-dependent and t-PA-independent mechanisms. Dose-dependent prolonged cyst growth occurred in the wild-type mice only. Early microglial activation and astrogliosis were similar in the wild-type and t-PA-/- mice. In adult mice (P45), demyelination occurred at the injection site in both groups but the astroglial scar was denser in the wild-type than in the t-PA-/- mice. These data support involvement of t-PA at several stages of WM lesion formation. Inactivation of t-PA might confer protection by prolonged hemostasis. The role of t-PA in cyst expansion suggests a new approach to the development of neuroprotective strategies in infants with developing WM lesions.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain Diseases / chemically induced
  • Brain Diseases / metabolism*
  • Brain Diseases / pathology*
  • Cysts / chemically induced
  • Cysts / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / administration & dosage
  • Excitatory Amino Acid Agonists / pharmacology
  • Glial Fibrillary Acidic Protein / metabolism
  • Ibotenic Acid / administration & dosage
  • Ibotenic Acid / pharmacology
  • Immunohistochemistry
  • Injections, Intraventricular
  • Mice
  • Mice, Knockout
  • Neuroglia / pathology
  • Time Factors
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*


  • Excitatory Amino Acid Agonists
  • Glial Fibrillary Acidic Protein
  • Ibotenic Acid
  • Tissue Plasminogen Activator