title: Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.
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.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.forename: Niza
authors.initials: N
authors.lastname: Nemkul
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Baumann
authors.forename: Ahmed
authors.initials: A
authors.lastname: Shereen
authors.forename: R Scott
authors.initials: RS
authors.lastname: Dunn
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lindquist
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000378:metabolism* / Q000517:prevention & control*; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D020925:Hypoxia-Ischemia, Brain / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D008070:Lipopolysaccharides; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator