Intracerebral Hematoma Contributes to Hydrocephalus After Intraventricular Hemorrhage via Aggravating Iron Accumulation

Abstract

I ntraventricular hemorrhage (IVH) occurs in 40% of patients with intracerebral hemorrhage (ICH). IVH is a severe complication of ICH 1 and is rarely (<3%) found in the absence of ICH. 2,3 Recent studies have shown that IVH and hydrocephalus are predictors of poor outcome after ICH. 4 Both human studies and preclinical studies on primary IVH or ICH with ventricular extension (ICH/IVH) are rare. However, some clinical studies have indicated that IVH, secondary to ICH, could lead to a higher risk of long term shunt dependent hydrocephalus compared with primary IVH. [5][6][7][8][9] Brain injury and hydrocephalus have not been systematically evaluated in relation to these 2 types of IVH in either humans or animals. 10 Recently, based on the most commonly used primary IVH rat model, we established a rat model of reproducible ICH/ IVH, which features characteristics of both ICH and IVH and closely mimics human IVH. 11Although it is well known that IVH is associated with hydrocephalus, the underlying mechanisms remain unclear. 10Recent studies have indicated that iron may play an important role in posthemorrhagic hydrocephalus and brain injury. [12][13][14][15] After disruption of the brain-cerebrospinal fluid (CSF) barrier because of IVH, intracerebral hematoma may provide a source of iron for release into the ventricular system via this breached barrier, eventually leading to brain damage.Thus, we hypothesized that ICH/IVH would generate more significant hydrocephalus and brain injury than IVH alone. This study examined this hypothesis by comparing the ICH/ IVH rat model with the primary IVH rat model. Moreover, we explored the potential role of intracerebral hematoma in brain iron deposition and hydrocephalus after ICH/IVH. MethodsOne hundred and sixty adult male Sprague-Dawley rats (250-350 g; the Third Military Medical University) were used. Animal use procedures were in compliance with the Guide for the Care and Use of Laboratory Animals and approved by the Animal Care and UseBackground and Purpose-The intraventricular hemorrhage (IVH) secondary to intracerebral hemorrhage (ICH) was reported to be relevant to a higher incidence of hydrocephalus, which would result in poorer outcomes for patients with ICH. However, the mechanisms responsible for this relationship remain poorly characterized. Thus, this study was designed to further explore the development and progression of hydrocephalus after secondary IVH. Methods-Autologous blood injection model was induced to mimic ICH with ventricular extension (ICH/IVH) or primary IVH in Sprague-Dawley rats. Magnetic resonance imaging, Morris water maze, brain water content, Evans blue extravasation, immunohistochemistry staining, Western blot, iron determination, and electron microscopy were used in these rats. Then, deferoxamine treatment was used to clarify the involvement of iron in the development of hydrocephalus. Chen et al Role of Intracerebral Hematoma in Hydrocephalus 2903Committee at the Third Military Medical University. Animals were anesthetized with pento...

Prolonged hydrocephalus induced by intraventricular hemorrhage in rats is reduced by curcumin therapy

“…The previous study on animal model corroborated the persistent existence of intraventricular iron overload in chronic phase of IVH [4]. Besides, the iron chelator, deferoxamine, reduced the concentrations of iron and ferritin in brain post-IVH induction and thereby decreased the incidence of post-hemorrhagic hydrocephalus [17].…”

Challenges for intraventricular hemorrhage research and emerging therapeutic targets

“…In a clinical study of infants with PHH, 75% had free iron present in their CSF, while no control subjects had such iron 84 . Significant evidence supports the notion that the accumulation of iron following IVH results in ventricular dilation and brain damage 10 . Moreover, it has been shown to correlate with brain edema, neuronal cell death in the basal ganglia, and motor function deficits 85 .…”

“…Some models utilize direct intracerebroventricular (ICV) injection 9 while others attempt to simulate combined ICH and IVH by injecting into peri-ventricular brain regions 10 . Ventricular injection provides a greater degree of control over the analysis by solely investigating the effects of intraventricular blood, but a parenchymal injection more fully replicates human IVH and induces greater damage 10 . In other studies, ICV injections of iron, lysed blood cells, hemoglobin, or thrombin have been used to study the effects of particular blood components 11–15 .…”

Hydrocephalus after Subarachnoid Hemorrhage: Pathophysiology, Diagnosis, and Treatment

“…Furthermore, necrosis of brain cells and disruption of BBB induced by iron are also depicted in rats [22], which makes this postulation more eloquent. Given all the previous research, preclinical research is supportive of the idea that oxidation accounts for the precise mechanisms of pathogenesis induced by iron [23], initially termed “ferroptosis” [24]. But more evidence is needed to further unravel the proceedings and connections between “ferroptosis” and HCP, and we are longing for a convincible clinical trial to testify whether removing the blood clot or subarachnoid blood lavage in the initial stage of SAH will have a definite positive outcome in these patients.…”