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

作者：Leroux Philippe^*; Omouendze Priscilla L; Roy Vincent; Dourmap Nathalie; Gonzalez Bruno J; Brasse Lagnel Carole; Carmeliet Peter; Leroux Nicollet Isabelle; Marret Stephane

来源：Journal of Neuropathology and Experimental Neurology, 2014, 73(5): 387-402.

DOI：10.1097/NEN.0000000000000062

• Brain hemorrhage
• Hyperactivity
• Mouse
• Neonate
• Plasminogen activator inhibitor 1 (PAI-1)
• Preterm
• Tissue plasminogen activator (t-PA)

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 L 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.

• 出版日期2014-5