Taming Neonatal Hypoxic–Ischemic Brain Injury by Intranasal Delivery of Plasminogen Activator Inhibitor-1
Background and Purpose—Plasminogen activator inhibitor-I (PAI-1), a ≈50-kDa serine protease inhibitor, markedly reduces the extravascular toxicity of tissue-type plasminogen activator in experimental hypoxic–ischemic (HI) brain injury of newborns. However, the current treatment with PAI-1 requires intracerebroventricle injection to cross the blood–brain barrier, which is an invasive procedure of limited clinical potential. Thus, we tested whether intranasal administration of PAI-1 can bypass blood–brain barrier and mitigate neonatal HI brain injury.
Methods—Rat pups were subjected to HI, with or without lipopolysaccharide pre-exposure, followed by intranasal delivery of a stable-mutant form of PAI-1 (CPAI).
Results—Immunoblotting showed that CPAI sequentially entered the olfactory bulbs and cerebral cortex after intranasal delivery and reduced ≈75% of brain atrophy in HI or lipopolysaccharide-sensitized HI injury. Mechanistically, CPAI attenuated HI-induced plasminogen activators and lipopolysaccharide/HI-induced nuclear factor-κB signaling, neuroinflammation, and blood–brain barrier permeability.
Conclusions—Intranasal delivery of CPAI is an effective treatment of experimental HI brain injury of newborns. Clinical application of this experimental therapy merits further investigation.
- intrauterine infection
- hypoxic-ischemic encephalopathy
- neonatal encephalopathy
- tissue-type plasminogen activator
- Received February 26, 2013.
- Accepted June 5, 2013.
- © 2013 American Heart Association, Inc.