Hepcidin Treatment Modulates the Expression of Divalent Metal Transporter-1, Ceruloplasmin, and Ferroportin-1 in the Rat Cerebral Cortex and Hippocampus

Lin, Li; Hölscher, Christian; Chen, Bingbing; Zhang, Zhifeng; Liu, Yueze

doi:10.1007/s12011-011-8967-3

Cited by 51 publications

(40 citation statements)

References 28 publications

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“…Ferroportin is also down-regulated when bound by hepcidin at the cell surface, an event that leads to the internalization and degradation of the iron carrier [35]. This was observed in rat brain when the expression of ferroportin was reduced following the intra-ventricular administration of hepcidin [79,80] or when hepcidin was added directly to primary cultures of neurons, astrocytes and microglia [69]. We found that hepcidin levels were reduced in human and mouse brains exhibiting severe AD pathology but early in the course of the disease, as shown in the mouse model, hepcidin levels did not differ significantly from controls and the interaction with ferroportin as seen in cortical neurons by immunohistochemical staining could contribute to the decline in levels of the iron carrier.…”

Section: Discussionmentioning

confidence: 99%

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Raha

Vaishnav

Friedland

et al. 2013

acta neuropathol commun

162

167

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BackgroundThe pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.ResultsProtein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.ConclusionOur results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.

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Section: Discussionmentioning

confidence: 99%

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Raha

Vaishnav

Friedland

et al. 2013

acta neuropathol commun

162

167

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“…28 Therefore, it can cause iron accumulation within the cell when overexpressed 29. Hepcidin expression is increased in response to cellular iron overload and inflammation 30.…”

Section: Iron Homeostasis In Normal Brainmentioning

confidence: 99%

Brain iron overload following intracranial haemorrhage

et al. 2016

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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.

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“…Hepcidin regulates cellular iron efflux by inducing internalization of ferroportin-1 (Fpn1) [7]. Li et al [8] have also found that hepcidin modulates the expression of ceruloplasmin (CP) and Fpn1 in rat cerebral cortex and hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Role of hepcidin and its downstream proteins in early brain injury after experimental subarachnoid hemorrhage in rats

Tan

Liu

et al. 2016

Mol Cell Biochem

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Early brain injury (EBI) is a major cause of mortality from subarachnoid hemorrhage (SAH). We aimed to study the pathophysiology of EBI and explore the role of hepcidin, a protein involved in iron homeostatic regulation, and its downstream proteins. One hundred and thirty-two male Sprague-Dawley rats were assigned into groups (n = 24/group): sham, SAH, SAH + hepcidin, SAH + hepcidin-targeting small interfering ribonucleic acid (siRNA), and SAH + scramble siRNA. Three hepcidin-targeting siRNAs and one scramble siRNA for hepcidin were injected 24 h before hemorrhage induction, and hepcidin protein was injected 30 min before induction. The rats were neurologically evaluated at 24 h and euthanized at 72 h. Hepcidin, ferroportin-1, and ceruloplasmin protein expression were measured by immunohistochemistry and Western blotting. Brain water content, blood-brain barrier (BBB) leakage, non-heme tissue iron and Garcia scale were evaluated. Hepcidin expression increased in the cerebral cortex and hippocampus after experimental SAH (P < 0.05 compared to sham), while ferroportin-1 and ceruloplasmin decreased (P < 0.05). Hepcidin injection lowered the expression of ferroportin-1 and ceruloplasmin further but siRNA reduced the levels of hepcidin (P < 0.05 compared to SAH) resulting in recovery of ferroportin-1 and ceruloplasmin levels. Apoptosis was increased in SAH rats compared to sham (P < 0.05) and increased slightly more by hepcidin, but decreased by siRNA (P < 0.05 compared to SAH). SAH rats had lower neurological scores, high brain water content, BBB permeability, and non-heme tissue iron (P < 0.05). In conclusion, downregulation of ferroportin-1 and ceruloplasmin caused by hepcidin enhanced iron-dependent oxidative damage and may be the potential mechanism of SAH.

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Hepcidin Treatment Modulates the Expression of Divalent Metal Transporter-1, Ceruloplasmin, and Ferroportin-1 in the Rat Cerebral Cortex and Hippocampus

Cited by 51 publications

References 28 publications

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Brain iron overload following intracranial haemorrhage

Role of hepcidin and its downstream proteins in early brain injury after experimental subarachnoid hemorrhage in rats

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