Hepcidin and its therapeutic potential in neurodegenerative disorders

Abstract

Abnormally high brain iron, resulting from the disrupted expression or function of proteins involved in iron metabolism in the brain, is an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia, and also plays a causative role in at least some of the other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia. As such, iron is believed to be a novel target for pharmacological intervention in these disorders. Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron‐related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood‐brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron‐associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

“…The consequent downregulation of Fpn is likely to increase the intracellular iron, creating a toxic environment by increasing ROS. Levels of hepcidin and redox-active iron are increased in AD brain tissue, supporting the above assumption [ 108 ]. Unlike systemic circulation, where excess iron is sequestered by the liver to protect vital organs, the brain and the retina lack such protection.…”

“…Although the brain and the eye are protected from fluctuations in circulating iron by the blood-brain and blood-retinal barriers, respectively, several cell types in the brain, retina, and anterior segment of the eye express hepcidin, suggesting additional regulation of iron exchange locally. In the brain, hepcidin is expressed in the cortex, hippocampus, cerebellum, thalamus, and medulla oblongata [ 108 , 109 , 110 ]. In the eye, the synthesis and expression of hepcidin is noted in several cell types in the retina and the anterior segment [ 111 , 112 , 113 ].…”

Overdosing on iron: Elevated iron and degenerative brain disorders

“…Increasing hepcidin levels in the brain has been suggested as a potential therapeutic approach for AD and other neurodegenerative diseases. 282,283 Consistently, hepcidin expression is reduced in the AD brain. 282,306 Administration of iron chelators has been tested as a the therapeutic strategies for AD.…”

“…31,280,281 Indeed, neuroprotection by elevating brain hepcidin has been described in other models of neurodegenerative disease. 282,283 Some studies have described that N-acetyl-cysteine (NAC), a modified form of cysteine (which increases GSH synthesis) can partially protect mice against neurodegeneration in cell culture and the MPTP model of PD. [284][285][286][287] NAC is likely to act downstream of iron accumulation to prevent oxidative stress.…”

Hepatocyte growth factor protects PC12 cells against OGD/R-induced injury by reducing iron

“…On the other hand, iron is also a major generator of reactive oxygen species (ROS) when it is increased abnormally in the brain. The iron-induced ROS are capable of damaging biological molecules and leading to neuronal injury [16,17]. Additionally, an excess of iron has been considered pathological in the ischemic brain, being a major source of ROS and a contributor to ischemia/reperfusion (I/R)or hypoxia/reoxygenation (H/R)-induced brain injury [18][19][20][21][22].…”