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Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance
Sruthi Ramagiri1, Shelei Pan1, Dakota DeFreitas1
1Department of Neurosurgery, Washington University School of Medicine, MO, 63110, St. Louis, USA.
Insights
An iron chelator, deferoxamine, administered during intraventricular hemorrhage in preterm infants, prevents posthemorrhagic hydrocephalus and sensorimotor deficits by promoting iron clearance and reducing choroid plexus injury.
Area of Science:
- Neonatal Neurology
- Pediatric Neurobiology
- Iron Metabolism in the Brain
Background:
- Posthemorrhagic hydrocephalus (PHH) affects up to 30% of preterm infants with high-grade intraventricular hemorrhage (IVH), leading to severe neurocognitive impairments.
- The exact mechanisms driving PHH remain unclear, but iron metabolic proteins, including hemoglobin, are suspected contributors to its pathogenesis.
- Iron accumulation in the choroid plexus and subsequent injury are implicated in the development of PHH.
Purpose of the Study:
- To establish a novel animal model for studying intraventricular hemorrhage (IVH)-induced hydrocephalus and associated pathologies.
- To investigate the therapeutic potential of the iron chelator deferoxamine in preventing PHH and neurological sequelae following IVH.
- To elucidate the role of iron clearance and choroid plexus function in the context of IVH.
Main Methods:
- Development of an animal model by intraventricular hemoglobin injection in PND4 neonates to induce acute and chronic hydrocephalus.
- Assessment of pathological changes including choroid plexus iron accumulation, injury, and expression of aquaporin-1, Na+/K+/Cl- cotransporter 1, and Na+/K+-ATPase.
- Evaluation of deferoxamine's efficacy when administered intraventricularly at the time of hemorrhage, assessing hydrocephalus development and sensorimotor gating deficits.
Main Results:
- The animal model successfully replicated key features of PHH, including hydrocephalus, choroid plexus iron deposition, and injury.
- Deferoxamine treatment significantly prevented hydrocephalus for up to 11 days and ameliorated sensorimotor gating deficits.
- Deferoxamine facilitated acute iron clearance, reduced choroid plexus iron levels, and reversed hemoglobin-induced aquaporin-1 upregulation.
Conclusions:
- Intraventricular administration of deferoxamine at the time of IVH is a promising therapeutic strategy for preventing PHH in preterm infants.
- Deferoxamine likely exerts its protective effects by enhancing iron clearance through the choroid plexus, thereby mitigating hemoglobin-induced injury.
- This study provides a valuable model for further research into PHH pathogenesis and treatment strategies.
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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