Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage

Neurosurgery. 2014 Dec;75(6):696-705; discussion 706. doi: 10.1227/NEU.0000000000000524.


Background: Neonatal germinal matrix hemorrhage/intraventricular hemorrhage is common and often results in hydrocephalus. The pathogenesis of posthemorrhagic hydrocephalus is not fully understood.

Objective: To explore the potential role of hemoglobin and iron released after hemorrhage.

Methods: Artificial cerebrospinal fluid (aCSF), hemoglobin, or iron was injected into the right lateral ventricle of postnatal day-7 Sprague Dawley rats. Ventricle size, heme oxygenase-1 (HO-1) expression, and the presence of iron were evaluated 24 and 72 hours after injection. A subset of animals was treated with an iron chelator (deferoxamine) or vehicle for 24 hours after hemoglobin injection, and ventricle size and cell death were evaluated.

Results: Intraventricular injection of hemoglobin and iron resulted in ventricular enlargement at 24 hours compared with the injection of aCSF. Protoporphyrin IX, the iron-deficient immediate heme precursor, did not result in ventricular enlargement after injection into the ventricle. HO-1, the enzyme that releases iron from heme, was increased in the hippocampus and cortex of hemoglobin-injected animals at 24 hours compared with aCSF-injected controls. Treatment with an iron chelator, deferoxamine, decreased hemoglobin-induced ventricular enlargement and cell death.

Conclusion: Intraventricular injection of hemoglobin and iron can induce hydrocephalus. Treatment with an iron chelator reduced hemoglobin-induced ventricular enlargement. This has implications for the pathogenesis and treatment of posthemorrhagic hydrocephalus.

Abbreviations: aCSF, artificial cerebrospinal fluidDAB, 3,3'-diaminobenzidine-4HClGMH-IVH, germinal matrix hemorrhage/intraventricular hemorrhageHO-1, heme oxygenase-1ICH, intracerebral hemorrhagePBS, phosphate-buffered salineSVZ, subventricular zoneTBST, tris-buffered saline with Tween 20.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Cerebral Hemorrhage / complications*
  • Cerebral Hemorrhage / metabolism
  • Cerebral Hemorrhage / physiopathology
  • Deferoxamine / pharmacology
  • Disease Models, Animal
  • Heme Oxygenase-1 / analysis
  • Heme Oxygenase-1 / biosynthesis
  • Hemoglobins / administration & dosage
  • Hemoglobins / toxicity*
  • Hydrocephalus / etiology*
  • Hydrocephalus / metabolism
  • Hydrocephalus / physiopathology
  • Immunohistochemistry
  • Injections, Intraventricular
  • Iron / administration & dosage
  • Iron / toxicity*
  • Lateral Ventricles / pathology
  • Male
  • Rats
  • Rats, Sprague-Dawley


  • Hemoglobins
  • Iron
  • Heme Oxygenase-1
  • Deferoxamine