Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage

DeGregorio-Rocasolano, Núria; Martí-Sistac, Octavi; Ponce, Jovita; Castelló-Ruiz, María; Millán, Mònica; Guirao, Verónica; García-Yébenes, Isaac; Salom, Juan B.; Ramos‐Cabrer, Pedro; Alborch, Enrique; Lizasoaín, Ignacio; Castillo, José; Dávalos, Antoni; Gasull, Teresa

doi:10.1016/j.redox.2017.11.026

Cited by 54 publications

(70 citation statements)

References 56 publications

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“…In MCAO animals, the iron intake was positively associated with the infarct volume ( Castellanos et al, 2002 ; García-Yébenes et al, 2012 ). Consistently, one in vitro study demonstrated that holo-transferrin increased ROS production, and caused neuronal cell death induced by deprivation of oxygen and glucose ( DeGregorio-Rocasolano et al, 2018 ). The experimental results also illustrated that administration of exogenous apotransferrin reduced brain damage and improved neurological outcomes with decreased lipid peroxidation, supporting the involvement of ferroptosis in ischemia ( DeGregorio-Rocasolano et al, 2018 ).…”

Section: The Role and Mechanism Of Ferroptosis In Acute Cns Injuriesmentioning

confidence: 76%

“…Consistently, one in vitro study demonstrated that holo-transferrin increased ROS production, and caused neuronal cell death induced by deprivation of oxygen and glucose ( DeGregorio-Rocasolano et al, 2018 ). The experimental results also illustrated that administration of exogenous apotransferrin reduced brain damage and improved neurological outcomes with decreased lipid peroxidation, supporting the involvement of ferroptosis in ischemia ( DeGregorio-Rocasolano et al, 2018 ). What’s more, the iron levels in the brain increased as humans age ( Ward et al, 2014 ), which may exacerbate ischemic stroke.…”

Section: The Role and Mechanism Of Ferroptosis In Acute Cns Injuriesmentioning

confidence: 76%

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Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

Shen

Lin

et al. 2020

Front. Cell Dev. Biol.

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Acute central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) present a grave health care challenge worldwide due to high morbidity and mortality, as well as limited clinical therapeutic strategies. Established literature has shown that oxidative stress (OS), inflammation, excitotoxicity, and apoptosis play important roles in the pathophysiological processes of acute CNS injuries. Recently, there have been many studies on the topic of ferroptosis, a form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxidation. Some studies have revealed an emerging connection between acute CNS injuries and ferroptosis. Ferroptosis, induced by the abnormal metabolism of lipids, glutathione (GSH), and iron, can accelerate acute CNS injuries. However, pharmaceutical agents, such as iron chelators, ferrostatin-1 (Fer-1), and liproxstatin-1 (Lip-1), can inhibit ferroptosis and may have neuroprotective effects after acute CNS injuries. However, the specific mechanisms underlying this connection has not yet been clearly elucidated. In this paper, we discuss the general mechanisms of ferroptosis and its role in stroke, TBI, and SCI. We also summarize ferroptosis-related drugs and highlight the potential therapeutic strategies in treating various acute CNS injuries. Additionally, this paper suggests a testable hypothesis that ferroptosis may be a novel direction for further research of acute CNS injuries by providing corresponding evidence.

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Section: The Role and Mechanism Of Ferroptosis In Acute Cns Injuriesmentioning

confidence: 76%

Section: The Role and Mechanism Of Ferroptosis In Acute Cns Injuriesmentioning

confidence: 76%

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

Shen

Lin

et al. 2020

Front. Cell Dev. Biol.

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“…However, more than one-half of patients fail to demonstrate clinical improvement (Yeo et al, 2013;Kikuchi et al, 2014). An increasing number of recent studies confirmed that free iron accumulates in the ipsilateral hypoxic-ischemic neonatal rat cortex (Palmer et al, 1999), total iron is increased significantly in the ischemic areas after ischemic stroke (Tuo et al, 2017), and the levels of transferrin receptors (TfRs) and iron-loaded transferrin (holo-transferrin, HTf) also increase after ischemic stroke (Park et al, 2011;DeGregorio-Rocasolano et al, 2018). All of this evidence indicates that a new cell death mechanism may play a very important role in EBI after ischemic stroke: ferroptosis (Dixon et al, 2012;Alim et al, 2019;Guan et al, 2019;Datta et al, 2020).…”

Section: Ischemic Strokementioning

confidence: 99%

The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease

Chen

Wang

et al. 2020

Front. Mol. Neurosci.

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Acute central nervous system (CNS) disease is very common and with high mortality. Many basic studies have confirmed the molecular mechanism of early brain injury (EBI) after acute CNS disease. Neuron death and dysfunction are important reasons for the neurological dysfunction in patients with acute CNS disease. Ferroptosis is a nonapoptotic form of cell death, the classical characteristic of which is based on the iron-dependent accumulation of toxic lipid reactive oxygen species. Previous studies have indicated that this mechanism is critical in the cell death events observed in many diseases, including cancer, tumor resistance, Alzheimer's disease, Parkinson's disease, stroke, and intracerebral hemorrhage (ICH). Ferroptosis may also play a very important role in EBI after acute CNS disease. Unresolved issues include the relationship between ferroptosis and other forms of cell death after acute CNS disease, the specific molecular mechanisms of EBI, the strategies to activate or inhibit ferroptosis to achieve desirable attenuation of EBI, and the need to find new molecular markers of ferroptosis that can be used to detect and study this process in vivo after acute CNS disease.

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“…In the cytosol, unused iron is stored into FT, a molecule composed of 24 subunits of a variable proportion of heavy and light chains, that shields up to 4500 iron atoms in a redox inert state. Neurons express both TfR1 and DMT1 (Pelizzoni et al, 2012; DeGregorio-Rocasolano et al, 2018); DMT1 is mainly found in the cytoplasm colocalizing with endosomes/lysosomes. Further, neurons express the iron export molecule FPN (Burdo et al, 2001; Zhou et al, 2017).…”

Section: Iron Uptake and Handling By Parenchymal Brain Cellsmentioning

confidence: 99%

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

DeGregorio-Rocasolano

2019

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In general, iron represents a double-edged sword in metabolism in most tissues, especially in the brain. Although the high metabolic demands of brain cells require iron as a redox-active metal for ATP-producing enzymes, the brain is highly vulnerable to the devastating consequences of excessive iron-induced oxidative stress and, as recently found, to ferroptosis as well. The blood–brain barrier (BBB) protects the brain from fluctuations in systemic iron. Under pathological conditions, especially in acute brain pathologies such as stroke, the BBB is disrupted, and iron pools from the blood gain sudden access to the brain parenchyma, which is crucial in mediating stroke-induced neurodegeneration. Each brain cell type reacts with changes in their expression of proteins involved in iron uptake, efflux, storage, and mobilization to preserve its internal iron homeostasis, with specific organelles such as mitochondria showing specialized responses. However, during ischemia, neurons are challenged with excess extracellular glutamate in the presence of high levels of extracellular iron; this causes glutamate receptor overactivation that boosts neuronal iron uptake and a subsequent overproduction of membrane peroxides. This glutamate-driven neuronal death can be attenuated by iron-chelating compounds or free radical scavenger molecules. Moreover, vascular wall rupture in hemorrhagic stroke results in the accumulation and lysis of iron-rich red blood cells at the brain parenchyma and the subsequent presence of hemoglobin and heme iron at the extracellular milieu, thereby contributing to iron-induced lipid peroxidation and cell death. This review summarizes recent progresses made in understanding the ferroptosis component underlying both ischemic and hemorrhagic stroke subtypes.

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Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage

Cited by 54 publications

References 56 publications

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

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