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

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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.

Copyright © 2014 by the American Association of Neuropathologists, Inc.

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