Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic Rats: Role of Endothelial Ferroptosis

Abdul, Yasir; Li, Weiguo; Ward, Rebecca; Abdelsaid, Mohammed; Hafez, Sherif; Dong, Guangkuo; Jamil, Sarah; Wolf, Victoria; Johnson, Maribeth H.; Fagan, Susan C.; Ergul, Adviye

doi:10.1007/s12975-020-00844-7

Cited by 87 publications

(63 citation statements)

References 61 publications

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“…In vivo, DFO also shows cardioprotective effects by inducing ischemic preconditioning-like effects in I/R models, and reduction of mice atherosclerotic lesion by inhibiting inflammation and impairing nitric oxide action [112][113][114]. In type 2 diabetic rat model, inhibition of ferroptosis by DFO treatment may prevent post-stroke cognitive impairment [115]. DFO administration showed cardioprotective effects in I/R models via inhibiting cytosolic ROS production and ferroptotic cell death [112].…”

Section: Iron Chelatorsmentioning

confidence: 99%

Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases

et al. 2021

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Ferroptosis, a recently identified and iron-dependent cell death, differs from other cell death such as apoptosis, necroptosis, pyroptosis, and autophagy-dependent cell death. This form of cell death does not exhibit typical morphological and biochemical characteristics, including cell shrinkage, mitochondrial fragmentation, nuclear condensation. The dysfunction of lipid peroxide clearance, the presence of redox-active iron as well as oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are three essential features of ferroptosis. Iron metabolism and lipid peroxidation signaling are increasingly recognized as central mediators of ferroptosis. Ferroptosis plays an important role in the regulation of oxidative stress and inflammatory responses. Accumulating evidence suggests that ferroptosis is implicated in a variety of cardiovascular diseases such as atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure, indicating that targeting ferroptosis will present a novel therapeutic approach against cardiovascular diseases. Here, we provide an overview of the features, process, function, and mechanisms of ferroptosis, and its increasingly connected relevance to oxidative stress, inflammation, and cardiovascular diseases.

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Section: Iron Chelatorsmentioning

confidence: 99%

Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases

et al. 2021

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“…DFO, developed over half a century ago, is the most potent and widely used of several FDA-approved iron chelators [ 17 , 18 ]. These therapeutics were originally developed to address systemic iron overload states such as transfusion-dependent thalassemia major but have since seen significant preclinical and clinical development for use across cancer [ 19 , 20 , 21 ], imaging [ 22 , 23 ], and neurological disease [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. DFO has a short plasma half-life and is typically challenging to deliver systemically, with most delivery methods involving long courses of intravenous (IV) infusion or intramuscular (IM) injection [ 43 ].…”

Section: The Development Of Deferoxamine and Intranasal Deliverymentioning

confidence: 99%

“…HIF-1α activates an elaborate transcriptional program designed as an organized cellular response to hypoxia, mediated principally by vascular endothelial growth factor (VEGF), erythropoietin (EPO), inducible nitric oxide synthase (iNOS), and insulin-like growth factor (IGF) [ 40 , 75 , 76 ]. By these pathways, iron chelators including IN DFO have been found to reverse the accumulation of protein aggregates [ 28 , 30 , 33 , 34 , 77 , 78 , 79 ], suppress neuroinflammation [ 31 , 38 , 77 , 80 , 81 , 82 , 83 , 84 ], protect against oxidative stress and neuronal injury [ 30 , 31 , 32 , 36 , 81 , 83 , 85 ], improve cerebrovascular function [ 25 , 37 , 40 , 76 ], activate pro-survival signaling pathways [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 76 ], bolster cerebral glucose metabolism [ 30 , 31 , 35 ], and strengthen synaptic function [ 35 , 86 , 87 ] ( Figure 1 ). In the follow...…”

Section: Iron Chelation and The Brainmentioning

confidence: 99%

“…Finally, there is evidence for the development of IN DFO in vascular dementia, the second leading cause of dementia worldwide. DFO has been shown to reverse cognitive deficits following hemorrhagic and ischemic vascular events in animal models, including events induced by diabetes [ 25 ]. Vascular dementia is a highly heterogenous entity involving generally stepwise cognitive decline secondary to progressive ischemic brain injury, and is at the crossroads of neurovascular dysfunction, neurodegeneration, and metabolic syndrome [ 129 ].…”

Section: In Dfo For Other Neurological Diseasesmentioning

confidence: 99%

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Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

et al. 2021

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Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.

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“…Additionally, rtPA continues to be the only FDA-approved pharmacological intervention for acute ischemic stroke (AIS) [8,9], despite multiple clinical trials exploring alternative treatments [10]. However, rtPA is not without side effects, and even when administered as indicated, it causes a 5.8% increase in the incidence of symptomatic hemorrhagic transformation [11,12]. In recent years, despite dozens of neuroprotective compounds demonstrating efficacy in animal models, multiple trials focusing on neuroprotection failed to produce positive results in patients [13].…”

Section: Introductionmentioning

confidence: 99%

Delayed Recanalization—How Late Is Not Too Late?

Kang

Gamdzyk

Tang

et al. 2020

Transl. Stroke Res.

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Stroke has become the second most prevalent cause of mortality in the world. Currently, the treatment of ischemic stroke is based on thrombolytic and thrombectomy therapy shortly after the ischemic event (≤ 4.5 h for thrombolytic strategies; ≤ 6 h for thrombectomy strategies). However, the majority of patients are unable to receive prompt treatment, particularly in undeveloped countries. Alternative solutions are lacking for those patients that miss the optimal window of opportunity for treatment. Recently, new developments in imaging techniques and intravascular interventional devices enable the expansion of the window of opportunity for treating stroke patients. Clinical studies have reported that delayed recanalization at 24 h, or even more than 1 month, was beneficial for some patients. However, the mechanisms of neuroprotection that underly the delayed recanalization in these ischemic stroke patients remain unclear. In this review, we will summarize the clinical studies of delayed recanalization, and organize them according to the duration of occlusion. Additionally, we will discuss the changing guidelines and possible mechanisms based on animal research, and attempt to draw conclusions and future perspectives.

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Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic Rats: Role of Endothelial Ferroptosis

Cited by 87 publications

References 61 publications

Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases

Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases

Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

Delayed Recanalization—How Late Is Not Too Late?

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