Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders

Bergsland, Niels; Schweser, Ferdinand; Jakimovski, Dejan; Hagemeier, Jesper; Dwyer, Michael G.; Zivadinov, Robert

doi:10.1007/s40263-019-00668-6

Cited by 13 publications

(11 citation statements)

References 159 publications

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“…Since iron is a cofactor in numerous enzymes in the nervous system including iron-sulfur cluster proteins in the mitochondria, heme-containing proteins such as hemoglobin or neuroglobin, and oxo-di-iron enzymes such as ribonucleotide reductase, it is important to understand the mechanism of action of iron chelation so one can understand how to nullify toxic levels of iron without interdicting physiological iron-dependent metalloenzymes. Initial hypotheses postulated that iron is toxic to neurons via its ability to act as a catalyst for the production of hydroxyl radicals from peroxide or peroxyl radicals from lipid peroxides, also known as Fenton chemistry, but the absence of good in vitro models of iron-mediated toxicity limited progress in understanding the mechanism of protection by iron chelators (Bergsland et al, 2019;Lee et al, 2019). Yonezawa et al (1996) used a model of glutamate-induced ferroptosis in immature oligodendrocytes to show that iron chelators are protective.…”

Section: Llmentioning

confidence: 99%

The Chemical Biology of Ferroptosis in the Central Nervous System

Ratan

2020

Cell Chemical Biology

122

100

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Over the past five decades, thanatology has come to include the study of how individual cells in our bodies die appropriately and inappropriately in response to physiological and pathological stimuli. Morphological and biochemical criteria have been painstakingly established to create clarity around definitions of distinct types of cell death and mechanisms for their activation. Among these, ferroptosis has emerged as a unique, oxidative stress-induced cell death pathway with implications for diseases as diverse as traumatic brain injury, hemorrhagic stroke, Alzheimer's disease, cancer, renal ischemia, and heat stress in plants. In this review, I highlight some of the formative studies that fostered its recognition in the nervous system and describe how chemical biological tools have been essential in defining events necessary for its execution. Finally, I discuss emerging opportunities for antiferroptotic agents as therapeutic agents in neurological diseases.

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Section: Llmentioning

confidence: 99%

The Chemical Biology of Ferroptosis in the Central Nervous System

Ratan

2020

Cell Chemical Biology

122

100

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“…Chelation therapy has shown promise in the diseases including AD, PD, autism, cancer, cardiovascular disease, etc. [269,270]. Chelating agents not only reduces raised metal concentration but some thiol based chelators, such as meso 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane 1-sulfonate (DMPS), D-pencillamine (DPA), and Monoisoamyldimercaptosuccinic acid (MiADMSA) ( Table 6) also have ROS neutralizing ability that can additionally diminish the augmented oxidative stress and further preventing cellular damage from oxidative insult [271].…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Patwa

Flora

2020

IJMS

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Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

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“…Most studies reported increased iron concentrations in the deep gray matter (DGM) (Stankiewicz, Neema, & Ceccarelli, 2014) and around plaques (Craelius, Migdal, Luessenhop, Sugar, & Mihalakis, 1982), and reduced iron concentrations within lesions (Haider et al, 2014; Kutzelnigg et al, 2005; Laule et al, 2013; Yao et al, 2012; Yao et al, 2014), in the normal‐appearing white matter (WM) (Hametner et al, 2013; Paling et al, 2012; Popescu et al, 2017; Yu et al, 2018), and in the thalamus (Bergsland et al, 2018; Burgetova et al, 2017; Khalil et al, 2015; Louapre et al, 2017; Pontillo et al, 2019; Schweser et al, 2018; Uddin, Lebel, Seres, Blevins, & Wilman, 2016; Zivadinov et al, 2018). The literature considers findings of increased region‐average iron concentrations as evidence for iron influx (Bergsland et al, 2019; Ndayisaba, Kaindlstorfer, & Wenning, 2019; Williams, Buchheit, Berman, & LeVine, 2012), whereas it is less clear how to interpret reduced iron concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…thalamus (Bergsland et al, 2018;Burgetova et al, 2017;Khalil et al, 2015;Louapre et al, 2017;Pontillo et al, 2019;Schweser et al, 2018;Uddin, Lebel, Seres, Blevins, & Wilman, 2016;Zivadinov et al, 2018). The literature considers findings of increased regionaverage iron concentrations as evidence for iron influx (Bergsland et al, 2019;Ndayisaba, Kaindlstorfer, & Wenning, 2019;Williams, Buchheit, Berman, & LeVine, 2012), whereas it is less clear how to interpret reduced iron concentrations.…”

mentioning

confidence: 99%

Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI

Schweser

Hagemeier

Dwyer

et al. 2020

Human Brain Mapping

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Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age‐ and sex‐matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing–remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease‐related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.

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Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders

Cited by 13 publications

References 159 publications

The Chemical Biology of Ferroptosis in the Central Nervous System

The Chemical Biology of Ferroptosis in the Central Nervous System

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI

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