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Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance

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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.

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Data Availability

The data that support the findings of this study may be available at the discretion of the corresponding author, upon reasonable request.

Abbreviations

GMH:

Germinal matrix hemorrhage

IVH:

Intraventricular hemorrhage

HB:

Hemoglobin

DFX:

Deferoxamine

PHH:

Posthemorrhagic hydrocephalus

ChP:

Choroid plexus

LV:

Lateral ventricle

AuNP:

Gold nanoparticle

PBS:

Phosphate buffered saline

PFA:

Paraformaldehyde

H&E:

Hematoxylin and eosin

AQP1:

Aquaporin-1

NKAT:

Sodium potassium ATPase

NKCC1:

Sodium potassium chloride cotransporter

DAPI:

4′,6-Diamidino-2-phenylindole

TUNEL:

Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling

EPM:

Elevated plus maze

PPI:

Prepulse inhibition

MWM:

Morris water maze

SEM:

Standard error of the mean

rm:

Repeated measures

CSP:

Cavum septum pellucidum

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Acknowledgements

The studies presented in this work were carried out, in part, using the Small Animal MR Facility of the Mallinckrodt Institute of Radiology, Hope Center Alafi Neuroimaging Lab, and Washington University Center for Cellular Imaging (WUCCI), supported by Washington University in St. Louis School of Medicine.

Funding

This study is funded by NIH R01 NS110793 (JMS), K12 Neurosurgeon Research Career Development Program (JMS), Hydrocephalus Association (JMS), WUCCI, McDonnell Centers for Systems Neuroscience and Cellular Neurobiology (JMS, DFW), Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital (JMS). The MRI studies presented in this work were carried out in the Small Animal MR Facility of the Mallinckrodt Institute of Radiology at Washington University (18–019, JMS).

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Author notes

  1. Sruthi Ramagiri, Shelei Pan, and Dakota DeFreitas contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, Washington University School of Medicine, MO, 63110, St. Louis, USA

    Sruthi Ramagiri, Shelei Pan, Dakota DeFreitas, Peter H. Yang, Dhvanii K. Raval, Prabagaran Esakky & Jennifer M. Strahle

  2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110-1093, USA

    David F. Wozniak

  3. Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, 63110-1093, USA

    David F. Wozniak

  4. Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, 63110-1093, USA

    David F. Wozniak

  5. Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Jennifer M. Strahle

  6. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Jennifer M. Strahle

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  1. Sruthi Ramagiri
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Ramagiri, S., Pan, S., DeFreitas, D. et al. Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance. Transl. Stroke Res. 14, 704–722 (2023). https://doi.org/10.1007/s12975-022-01092-7

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