Funded by the National Institutes of Health
Funding Years: 2012-2017
Intraventricular hemorrhage (IVH) occurs in many patients with intracerebral and subarachnoid hemorrhage (SAH). Recent studies have found IVH is a predictor of poor outcome after intracerebral hemorrhage and that hydrocephalus develops in 55% intracerebral hemorrhage patients with IVH. Hydrocephalus is also a major problem in SAH. Early hydrocephalus occurs in 20-50% SAH patients and is associated with poor clinical grade. However, the mechanisms of IVH-induced hydrocephalus are not well understood. Lysis of erythrocytes results in iron accumulation in the brain and causes brain damage after intracerebral hemorrhage. However, the role of erythrocyte lysis and iron toxicity in IVH-induced brain injury and hydrocephalus has still to be elucidated. Erythrocyte lysis after IVH may start very early. Hemoglobin released from red blood cells reaches its peak concentration by the second day following injection of blood into the cerebrospinal fluid of dogs. Hemoglobin release, from lysis of erythrocytes in human intracranial hemorrhage, increases during the first few days. Erythrocyte lysis appears to result from either depletion of intracellulr energy reserves or activation of the complement system. We have established an IVH model in rats and long-term ventricular dilatation has been observed. Recently we have found that hydrocephalus occurs in a model of SAH which results in intraventricular blood. Our preliminary data have demonstrated: 1) Intraventricular injection of autologous whole blood causes iron accumulation, hydrocephalus, neuronal death and brain tissue loss in the hippocampus; 2) Intraventricular injection of lysed erythrocytes rather than packed erythrocytes causes hydrocephalus by 24 hours; 3) Heme oxygenase-1 and ferritin levels are increased significantly in the hippocampus and periventricular areas following IVH; 4) Intraventricular injection of iron alone can also result in acute hydrocephalus; 5) Deferoxamine, an iron chelator, reduces IVH-induced hydrocephalus and hippocampal tissue loss. In this application, we propose to test the following specific aims: 1) Determine whether erythrocyte lysis and hemoglobin release cause hydrocephalus and neuronal death following IVH; 2) Determine whether complement inhibition reduces erythrocyte lysis and IVH/SAH-induced brain injury; 3) Examine the natural time courses of iron buildup, oxidative stress and upregulation of iron handling proteins in the brain after IVH; 4) Determine whether heme oxygenase inhibition reduces heme degradation and IVH/SAH-induced brain injury; and 5) Determine whether iron chelation reduces oxidative stress, hydrocephalus and neuronal death after IVH/SAH in aged rats. The purpose of our project is to investigate the mechanisms of brain injury after IVH. The long-term goal of our studies is to limit hemorrhagic brain damage in patients.
PI(s): Guohua Xi
Co-I(s): Ya Hua, Richard Keep, Lewis Morgenstern