Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia

Dianer Yang, Yu Yo Sun, Niza Nemkul, Jessica M. Baumann, Ahmed Shereen, R. Scott Dunn, Marsha Wills-Karp, Daniel A. Lawrence, Diana M. Lindquist, Chia Yi Kuan

Research output: Contribution to journalArticle

Abstract

Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.

Original languageEnglish (US)
Pages (from-to)1218-1229
Number of pages12
JournalCerebral Cortex
Volume23
Issue number5
DOIs
StatePublished - May 1 2013
Externally publishedYes

Keywords

  • diffusion tensor imaging (DTI)
  • neonatal hypoxia-ischemia
  • plasminogen activator inhibitor-1 (PAI-1)
  • tissue plasminogen activator (tPA)
  • white matter injury

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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  • Cite this

    Yang, D., Sun, Y. Y., Nemkul, N., Baumann, J. M., Shereen, A., Dunn, R. S., Wills-Karp, M., Lawrence, D. A., Lindquist, D. M., & Kuan, C. Y. (2013). Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia. Cerebral Cortex, 23(5), 1218-1229. https://doi.org/10.1093/cercor/bhs115