Dianer Yang1,2, Yu-Yo Sun1,2, Xiaoyi Lin2, Jessica M Baumann1, Mark Warnock3, Daniel A Lawrence3, Chia-Yi Kuan1,2. 1. Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center. Cincinnati, OH 45229. 2. Division of Neurology, Department of Pediatrics; the Center for Neurodegenerative Disease (CND), the Emory University School of Medicine, Atlanta, GA 30322. 3. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
Abstract
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.
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.
Authors: Suzanne Craft; Laura D Baker; Thomas J Montine; Satoshi Minoshima; G Stennis Watson; Amy Claxton; Matthew Arbuckle; Maureen Callaghan; Elaine Tsai; Stephen R Plymate; Pattie S Green; James Leverenz; Donna Cross; Brooke Gerton Journal: Arch Neurol Date: 2011-09-12
Authors: 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 Journal: Cereb Cortex Date: 2012-05-03 Impact factor: 5.357
Authors: Pia Wintermark; Theonia Boyd; Matthew C Gregas; Michelle Labrecque; Anne Hansen Journal: Am J Obstet Gynecol Date: 2010-09-20 Impact factor: 8.661
Authors: Xiaoying Wang; Kiyoshi Tsuji; Sun-Ryung Lee; MingMing Ning; Karen L Furie; Alastair M Buchan; Eng H Lo Journal: Stroke Date: 2004-09-30 Impact factor: 7.914
Authors: Dianer Yang; Niza Nemkul; Ahmed Shereen; Alice Jone; R Scott Dunn; Daniel A Lawrence; Diana Lindquist; Chia-Yi Kuan Journal: J Neurosci Date: 2009-07-08 Impact factor: 6.167
Authors: Hong-Ru Chen; Xiaohui Zhang-Brotzge; Yury M Morozov; Yuancheng Li; Siming Wang; Helen Heju Zhang; Irena S Kuan; Elizabeth M Fugate; Hui Mao; Yu-Yo Sun; Pasko Rakic; Diana M Lindquist; Ton DeGrauw; Chia-Yi Kuan Journal: JCI Insight Date: 2021-09-08