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.
Highlights
Perinatal hypoxic–ischemic (HI) insult is a major threat to the development of cerebral cortex (Volpe 2003; Khwaja and Volpe 2008)
These findings suggest that hyper-stimulation of the parenchymal type plasminogen activator (tPA) activity is an important mechanism of neonatal HI brain injury, but whether CPAI protects against infection-sensitized HI injury is unknown
Growing evidences indicate that intrauterine infection activates fetal inflammatory response and causes greater HI brain injury in infants, but effective therapies of this condition remain unavailable for several reasons
Summary
Perinatal hypoxic–ischemic (HI) insult is a major threat to the development of cerebral cortex (Volpe 2003; Khwaja and Volpe 2008). Studies in animal models suggested that prenatal infection (chorioamnionitis) and the ensuing fetal inflammatory response amplify brain damage via innate immunity and microglia activation (Lehnardt et al 2003; Eklind et al 2005) These discoveries, have not led to effective therapies, because systemic immune suppression in infants will increase the risk of severe infection, which already accounts for up to 25% of neonatal death (Lawn et al 2005). We recently reported that anti-tPA treatment with a stable-mutant form of plasminogen activator inhibitor-1 (PAI-1) called CPAI markedly reduced HItriggered tPA proteolytic activity and destruction of newborn brains (Berkenpas et al 1995; Adhami et al 2008; Yang et al 2009) These findings suggest that hyper-stimulation of the parenchymal tPA activity is an important mechanism of neonatal HI brain injury, but whether CPAI protects against infection-sensitized HI injury is unknown
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