Role of tissue-derived plasminogen activator (t-PA) in an excitotoxic mouse model of neonatal white matter lesions.
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.
Hennebert
Olivier
O
MERCI, UPRES EA 2122, Faculty of Medicine and Pharmacy, Rouen University, Rouen, France.
Marret
Stéphane
S
Carmeliet
Peter
P
Gressens
Pierre
P
Laquerrière
Annie
A
Leroux
Philippe
P
D000818:Animals; D000831:Animals, Newborn; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D003560:Cysts / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007051:Ibotenic Acid / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D007051:Ibotenic Acid; D010959:Tissue Plasminogen Activator