Therapeutic administration of plasminogen activator inhibitor-1 prevents hypoxic-ischemic brain injury in newborns.
Disruption of the integrity of the blood-brain barrier (BBB) is an important mechanism of cerebrovascular diseases, including neonatal cerebral hypoxia-ischemia (HI). Although both tissue-type plasminogen activator (tPA) and matrix metalloproteinase-9 (MMP-9) can produce BBB damage, their relationship in neonatal cerebral HI is unclear. Here we use a rodent model to test whether the plasminogen activator (PA) system is critical for MMP-9 activation and HI-induced brain injury in newborns. To test this hypothesis, we examined the therapeutic effect of intracerebroventricular injection of plasminogen activator inhibitor-1 (PAI-1) in rat pups subjected to unilateral carotid artery occlusion and systemic hypoxia. We found that the injection of PAI-1 greatly reduced the activity of both tPA and urokinase-type plasminogen activator after HI. It also blocked HI-induced MMP-9 activation and BBB permeability at 24 h of recovery. Furthermore, magnetic resonance imaging and histological analysis showed the PAI-1 treatment reduced brain edema, axonal degeneration, and cortical cell death at 24-48 h of recovery. Finally, the PAI-1 therapy provided a dose-dependent decrease of brain tissue loss at 7 d of recovery, with the therapeutic window at 4 h after the HI insult. Together, these results suggest that the brain PA system plays a pivotal role in neonatal cerebral HI and may be a promising therapeutic target in infants suffering hypoxic-ischemic encephalopathy.
Yang
Dianer
D
Division of Developmental Biology and Division of Neurology, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Nemkul
Niza
N
Shereen
Ahmed
A
Jone
Alice
A
Dunn
R Scott
RS
Lawrence
Daniel A
DA
Lindquist
Diana
D
Kuan
Chia-Yi
CY
D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000503:physiopathology* / Q000517:prevention & control*; D007276:Injections, Intraventricular; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage*; D011480:Protease Inhibitors / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage
D061965:Matrix Metalloproteinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D020780:Matrix Metalloproteinase 9