Role of Red Blood Cell Lysis and Iron in Hydrocephalus after Intraventricular Hemorrhage

Abstract

Thrombin and iron are two major players in intracerebral hemorrhage-induced brain injury and our recent study found that thrombin contributes to hydrocephalus development in a rat model of intraventricular hemorrhage (IVH). This study investigated the role of red blood cell (RBC) lysis and iron in hydrocephalus after IVH. There were three parts to this study. First, male SpragueDawley rats received an injection of saline, packed, or lysed RBCs into the right lateral ventricle. Second, rats had an intraventricular injection of iron or saline. Third, the rats received intraventricular injection of lysed RBCs mixed with deferoxamine (0.5 mg in 5 mL saline) or saline. All rats underwent magnetic resonance imaging at 24 hours and were then euthanized for brain edema measurement, western blot analysis, or brain histology. We found that intraventricular injection of lysed RBCs, but not packed RBCs, resulted in ventricular enlargement and marked increases in brain heme oxygenase-1 and ferritin at 24 hours. Intraventricular injection of iron also resulted in ventricular enlargement and ventricular wall damage 24 hours later. Coinjection of deferoxamine reduced lysed RBC-induced ventricular enlargement (Po0.01). These results suggest that iron, a degradation product of hemoglobin, has an important role in hydrocephalus development after IVH.

Protease-Activated Receptor 1 and 4 Signal Inhibition Reduces Preterm Neonatal Hemorrhagic Brain Injury

“…p-mTOR mediated) that are potentially upstream of ECM protein dysregulation. 1, 5, 7–9, 11, 14 Multiple parallels (especially thrombin) 1, 2, 7–11 exist between our study, and the pathophysiology of adult intracerebral hemorrhage. 4, 5, 12–14 Thus in extension: our findings may have a much broader therapeutic implication in terms of further adult stroke mechanistic study (for detailed comparisons, however—please reference 15 , these fall outside the scope of this paper).…”

Role of Hemoglobin and Iron in Hydrocephalus After Neonatal Intraventricular Hemorrhage

“…5, 6, 26-28 Neonatal animal models of IVH have primarily examined the impact of blood within the ventricle 9, 29, 30 but have not addressed the role of specific components of blood in the pathogenesis of hydrocephalus. As iron and hemoglobin metabolites are present in CSF after ICH or IVH, 11, 12, 31 they may play a role in ventricular enlargement.…”

Intraventricular Fibrinolysis with Tissue Plasminogen Activator is Associated with Transient Cerebrospinal Fluid Inflammation: A Randomized Controlled Trial

“…37 Heme itself may be neurotoxic and may induce inflammation, before being degraded into carbon monoxide, biliverdin, and iron by the enzyme heme oxygenase, which becomes markedly upregulated in glial cells in the context of SAH. 4,6,9,38 Iron subsequently accumulates in glial cells and astrocytes, and also reacts with hydrogen peroxide to form reactive oxygen species, which in turn induces oxidative injury and exacerbates inflammation. 4,8,38 It is now well established by randomized trials that pharmacological use of intraventricular TPA accelerates hematoma clearance, both from the ventricles and basal cisterns.…”

“…[1][2][3] The accumulation of hemoglobin breakdown derivatives, including iron, bilirubin oxidation products, and oxygen-free radicals, contributes to early brain injury and a higher risk of hydrocephalus and delayed cerebral ischemia. [4][5][6] The presence of blood in the ventricular and subarachnoid spaces induces inflammation, which may be an additional important mechanism contributing to early and delayed brain injury. [7][8][9][10] These observations provide a rationale for therapeutic measures aimed at accelerating the clearance of blood.…”