Brain iron overload following intracranial haemorrhage

Abstract

Intracranial haemorrhages, including intracerebral haemorrhage (ICH), intraventricular haemorrhage (IVH) and subarachnoid haemorrhage (SAH), are leading causes of morbidity and mortality worldwide. In addition, haemorrhage contributes to tissue damage in traumatic brain injury (TBI). To date, efforts to treat the long-term consequences of cerebral haemorrhage have been unsatisfactory. Incident rates and mortality have not showed significant improvement in recent years. In terms of secondary damage following haemorrhage, it is becoming increasingly apparent that blood components are of integral importance, with haemoglobin-derived iron playing a major role. However, the damage caused by iron is complex and varied, and therefore, increased investigation into the mechanisms by which iron causes brain injury is required. As ICH, IVH, SAH and TBI are related, this review will discuss the role of iron in each, so that similarities in injury pathologies can be more easily identified. It summarises important components of normal brain iron homeostasis and analyses the existing evidence on iron-related brain injury mechanisms. It further discusses treatment options of particular promise.

Challenges for intraventricular hemorrhage research and emerging therapeutic targets

“…DFX co-injection reduces ventricular enlargement following ICV injection of lysed erythrocytes 12 , hemoglobin, and iron injection in both adults and neonates 14 . While it is most likely DFX acts via iron chelation, it is possible that it can also affect important signaling pathways 94 . The Wnt signaling pathway plays a role in the coagulation cascade, and may be involved in the formation of obstructive non-communicating hydrocephalus following IVH.…”

The Dual Role of Hepcidin in Brain Iron Load and Inflammation

“…But, iron excess is toxic for brain cells. This is observed during brain hemorrhage, where inflammatory signaling is responsible for the increase in brain iron load, which is associated with oxidative damage and cognitive decline ( Wu et al, 2003 ; Ward et al, 2014 ; Garton et al, 2016 ). Furthermore, iron dysregulation has been proposed as a pathogenic factor in neurodegenerative diseases as well ( Ward et al, 2014 ).…”

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

“…Specifically, the H63D variant of the HFE gene [22.9% of gene variants worldwide (6)] has received increased attention because of a greater susceptibility to elevated iron and oxidative damage in the brain (7,8). In addition to genetic factors, brain iron accumulation can also be caused by nongenetic factors, such as traumatic brain injury (21 million people per year worldwide) (9, 10), intracranial hemorrhage (1.75 million incidents per year worldwide) (11,12), and natural aging (13).…”