List of publications for November 13, 2022
Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance
(2022) Translational Stroke Research, .
Ramagiri, S.a , Pan, S.a , DeFreitas, D.a , Yang, P.H.a , Raval, D.K.a , Wozniak, D.F.b c d , Esakky, P.a , Strahle, J.M.a e f
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110-1093, United States
c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110-1093, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110-1093, United States
e Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Posthemorrhagic hydrocephalus occurs in up to 30% of infants with high-grade intraventricular hemorrhage and is associated with the worst neurocognitive outcomes in preterm infants. The mechanisms of posthemorrhagic hydrocephalus after intraventricular hemorrhage are unknown; however, CSF levels of iron metabolic pathway proteins including hemoglobin have been implicated in its pathogenesis. Here, we develop an animal model of intraventricular hemorrhage using intraventricular injection of hemoglobin at post-natal day 4 that results in acute and chronic hydrocephalus, pathologic choroid plexus iron accumulation, and subsequent choroid plexus injury at post-natal days 5, 7, and 15. This model also results in increased expression of aquaporin-1, Na+/K+/Cl- cotransporter 1, and Na+/K+/ATPase on the apical surface of the choroid plexus 24 h post-intraventricular hemorrhage. We use this model to evaluate a clinically relevant treatment strategy for the prevention of neurological sequelae after intraventricular hemorrhage using intraventricular administration of the iron chelator deferoxamine at the time of hemorrhage. Deferoxamine treatment prevented posthemorrhagic hydrocephalus for up to 11 days after intraventricular hemorrhage and prevented the development of sensorimotor gating deficits. In addition, deferoxamine treatment facilitated acute iron clearance through the choroid plexus and subsequently reduced choroid plexus iron levels at 24 h with reversal of hemoglobin-induced aquaporin-1 upregulation on the apical surface of the choroid plexus. Intraventricular administration of deferoxamine at the time of intraventricular hemorrhage may be a clinically relevant treatment strategy for preventing posthemorrhagic hydrocephalus and likely acts through promoting iron clearance through the choroid plexus to prevent hemoglobin-induced injury. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Deferoxamine; Germinal matrix hemorrhage; Hydrocephalus; Intraventricular hemorrhage; Preterm
Funding details
National Institutes of HealthNIHR01 NS110793
McDonnell Center for Systems Neuroscience
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
Hydrocephalus AssociationHA
St. Louis Children’s HospitalSLCH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus