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The Journal of Neuroscience, July 8, 2009, 29(27):8669-8674; doi:10.1523/JNEUROSCI.1117-09.2009

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Brief Communications
Therapeutic Administration of Plasminogen Activator Inhibitor-1 Prevents Hypoxic–Ischemic Brain Injury in Newborns

Dianer Yang,¹ Niza Nemkul,¹ Ahmed Shereen,² Alice Jone,¹ R. Scott Dunn,² Daniel A. Lawrence,³ Diana Lindquist,² and Chia-Yi Kuan¹

¹Division of Developmental Biology and Division of Neurology, ²Imaging Research Center, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and ³Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109

Correspondence should be addressed to Dr. Chia-Yi Kuan, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. Email: alex.kuan{at}cchmc.org

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.

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Received March 7, 2009; revised May 8, 2009; accepted June 1, 2009.

Correspondence should be addressed to Dr. Chia-Yi Kuan, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. Email: alex.kuan{at}cchmc.org

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