title: Anti-tissue plasminogen activator (tPA) as an effective therapy of neonatal hypoxia-ischemia with and without inflammation.
abstract: Hypoxic-ischemic brain injury is an important cause of neurodevelopmental deficits in neonates. Intrauterine infection and the ensuing fetal inflammatory responses augment hypoxic-ischemic brain injury and attenuate the efficacy of therapeutic hypothermia. Here, we review evidences from preclinical studies suggesting that the induction of brain parenchymal tissue-type plasminogen activator (tPA) plays an important pathogenic role in these conditions. Moreover, administration of a stable-mutant form of plasminogen activator inhibitor-1 called CPAI confers potent protection against hypoxic-ischemic injury with and without inflammation via different mechanisms. Besides intracerebroventricular injection, CPAI can also be administered into the brain using a noninvasive intranasal delivery strategy, adding to its applicability in clinical use. In sum, the therapeutic potential of CPAI in neonatal care merits further investigation with large-animal models of hypoxia-ischemia and cerebral palsy.
authors.affiliation: Department of Pediatrics, Children's Healthcare of Atlanta; Center for Neurodegenerative Disease (CND), Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D015849:Plasminogen Inactivators / Q000008:administration & dosage*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors
chemical_list: D018696:Neuroprotective Agents; D015849:Plasminogen Inactivators; D010959:Tissue Plasminogen Activator
keywords: Cerebral palsy; Chorioamnionitis; Intranasal; Plasminogen activator inhibitor-1