Skip Navigation LinksHome > May 2014 - Volume 73 - Issue 5 > Age-Dependent Neonatal Intracerebral Hemorrhage in Plasminog...
Journal of Neuropathology & Experimental Neurology:
doi: 10.1097/NEN.0000000000000062
Original Articles

Age-Dependent Neonatal Intracerebral Hemorrhage in Plasminogen Activator Inhibitor 1 Knockout Mice

Leroux, Philippe PhD; Omouendze, Priscilla L. PhD; Roy, Vincent PhD; Dourmap, Nathalie PhD; Gonzalez, Bruno J. PhD; Brasse-Lagnel, Carole PhD; Carmeliet, Peter MD, PhD; Leroux-Nicollet, Isabelle PhD; Marret, Stéphane MD, PhD

Supplemental Author Material
Collapse Box


Abstract: Intracerebral-intraventricular hemorrhages (ICH/IVH) in very preterm neonates are responsible for high mortality and subsequent disabilities. In humans, tissue plasminogen activator (t-PA) initiates fibrinolysis and activates endoluminal-endothelial receptors; dysfunction of the t-PA inhibitor (PAI-1) results in recurrent hemorrhages. We used PAI-1 knockout (PAI-1−/−) mice to examine the role of t-PA in age-dependent intracranial hemorrhages as a possible model of preterm ICH/IVH. Intracortical injection of 2 μL of phosphate-buffered saline produced a small traumatic injury and a high rate of hemorrhage in PAI-1−/− pups at postnatal day 3 (P3) or P5, whereas it had no effect in wild-type neonates. This resulted in white matter and cortical lesions, ventricle enlargement, hyperlocomotion, and altered cortical levels of serotonin and dopamine in the adult PAI−/− mice. N-methyl-D-aspartate receptor blockers, plasmin- and matrix metalloproteinases inhibitors reduced hemorrhage and tissue lesions. In contrast to P3 to P5, no significant hemorrhages were induced in P10 PAI-1−/− pups and there were no behavioral or neurochemical alterations in adulthood. These data suggest that microvascular immaturity up to P5 in mice is a determinant factor required for t-PA–dependent vascular rupture. Neonatal PAI-1−/− mice could be a useful ICH/IVH model for studying the ontogenic window of vascular immaturity and vascular protection against later neurodisabilities.

© 2014 by American Association of Neuropathologists, Inc.


Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.