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Therapeutic Advances in Rare Disease 2022The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature... (Review)
Review
OBJECTIVES
The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease.
METHODS
Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched.
RESULTS
Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone ( = 11), followed by recombinant erythropoietin ( = 6), omaveloxolone ( = 3), and amantadine hydrochloride ( = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, = 12), the Scale for Assessment and Rating of Ataxia (SARA, = 7), and the Activities of Daily Living scale (ADL, = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation ( = 1), craniocerebral injury ( = 1), and ventricular tachycardia ( = 1).
CONCLUSION
Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.
PubMed: 37180421
DOI: 10.1177/26330040221139872 -
Scientific Reports Oct 2023NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms...
NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms of NMDA excitotoxicity will provide further insight into the mechanisms of many retinal diseases. To study mechanisms of NMDA excitotoxicity in vivo, we used an animal model in which NMDA (20 mM, 2 µL) was injected into the vitreous of mice. We also used high-throughput expression profiling, various animals with reduced expression of target genes, and animals treated with the oral iron chelator deferiprone. We found that the expression of many genes involved in inflammation, programmed cell death, free radical production, oxidative stress, and iron and calcium signaling was significantly increased 24 h after NMDA treatment. Meanwhile, decreased activity of the pro-inflammatory TNF signaling cascade and decreased levels of ferrous iron (Fe, required for free radical production) led to significant neuroprotection in NMDA-treated retinas. Since increased TNF signaling activity and high Fe levels trigger regulated necrosis, which, in turn, lead to inflammation, we proposed an important role in NMDA excitotoxicity of a positive feedback loop in which regulated necrosis promotes inflammation, which subsequently triggers regulated necrosis.
Topics: Mice; Animals; N-Methylaspartate; Retina; Retinal Diseases; Necrosis; Iron; Free Radicals; Inflammation
PubMed: 37891222
DOI: 10.1038/s41598-023-45855-0 -
Biomedicine & Pharmacotherapy =... Aug 2023Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by massive loss of specific neurons. It is a progressive disabling, severe and fatal... (Review)
Review
Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by massive loss of specific neurons. It is a progressive disabling, severe and fatal complex disease. Due to its complex pathogenesis and limitations of clinical treatment strategies, it poses a serious medical challenge and medical burden worldwide. The pathogenesis of AD is not clear, and its potential biological mechanisms include aggregation of soluble amyloid to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFT), neuroinflammation, ferroptosis, oxidative stress and metal ion disorders. Among them, ferroptosis is a newly discovered programmed cell death induced by iron-dependent lipid peroxidation and reactive oxygen species. Recent studies have shown that ferroptosis is closely related to AD, but the mechanism remains unclear. It may be induced by iron metabolism, amino acid metabolism and lipid metabolism affecting the accumulation of iron ions. Some iron chelating agents (deferoxamine, deferiprone), chloroiodohydroxyquine and its derivatives, antioxidants (vitamin E, lipoic acid, selenium), chloroiodohydroxyquine and its derivatives Fer-1, tet, etc. have been shown in animal studies to be effective in AD and exert neuroprotective effects. This review summarizes the mechanism of ferroptosis in AD and the regulation of natural plant products on ferroptosis in AD, in order to provide reference information for future research on the development of ferroptosis inhibitors.
Topics: Animals; Alzheimer Disease; Ferroptosis; Biological Products; Iron; Metals
PubMed: 37210894
DOI: 10.1016/j.biopha.2023.114312 -
Neurotherapeutics : the Journal of the... Sep 2022Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response...
Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala.
Topics: Animals; Mice; Deferiprone; Selective Serotonin Reuptake Inhibitors; Iron; Serotonin Plasma Membrane Transport Proteins; Serotonin; Depression; Antidepressive Agents; Disease Models, Animal; Iron Chelating Agents
PubMed: 35861925
DOI: 10.1007/s13311-022-01257-0 -
Annals of Neurology Jun 2021Superficial siderosis of the central nervous system results from subpial hemosiderin deposition due to chronic low-grade bleeding into the subarachnoid space. The... (Review)
Review
Superficial siderosis of the central nervous system results from subpial hemosiderin deposition due to chronic low-grade bleeding into the subarachnoid space. The confluent and marginal subpial hemosiderin is best appreciated on iron-sensitive magnetic resonance imaging sequences. With widespread use of magnetic resonance imaging, the disorder is increasingly being recognized, including in asymptomatic individuals. Gait ataxia, often with hearing impairment is a common clinical presentation. A clinical history of subarachnoid hemorrhage is generally not present. A macrovascular pathology is generally not causative. The most common etiology is dural disease, often dural tears. Prior or less commonly ongoing symptoms of craniospinal hypovolemia may be present. Common etiologies for dural tears include disc disease and trauma, including surgical trauma. Patients with dural tears due to herniated and calcified discs often have a ventral intraspinal fluid collection due to cerebrospinal fluid leak. A precise identification of the dural tear relies on multimodality imaging. It has been speculated that chronic bleeding from fragile blood vessels around the dural tear may be the likely underlying mechanism. Surgical correction of the bleeding source is a logical therapeutic strategy. Clinical outcomes are variable, although neuroimaging evidence of successful dural tear repair is noted. The currently available data regarding use of deferiprone in patients with superficial siderosis is insufficient to recommend its routine use in patients. ANN NEUROL 2021;89:1068-1079.
Topics: Hemosiderin; Humans; Subarachnoid Hemorrhage
PubMed: 33860558
DOI: 10.1002/ana.26083 -
British Journal of Pharmacology Jan 2023Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has...
BACKGROUND AND PURPOSE
Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long-term effects of TBI remains unknown.
EXPERIMENTAL APPROACH
We investigated the role of iron and the effect of therapeutic intervention using a brain-permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3-month period post-TBI.
KEY RESULTS
Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis, microglia/macrophages and preservation of neurons in the injured brain at 2 weeks and/or 1 month post-TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores, locomotor/gait performance and cognitive function, and attenuated anxiety-like symptoms post-TBI. Deferiprone reduced iron levels, lipid peroxidation/oxidative stress and altered expression of neurotrophins in the injured brain over this period.
CONCLUSION AND IMPLICATIONS
Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI.
Topics: Animals; Mice; Deferiprone; Quality of Life; Mice, Inbred C57BL; Brain Injuries, Traumatic; Iron
PubMed: 36102035
DOI: 10.1111/bph.15950 -
Saudi Journal of Biological Sciences Apr 2022Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron... (Review)
Review
Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron metabolism. Its normal value is between 10 and 200 ngmL in men and between 30 and 300 ngmL in women. Iron is delivered to the tissue via them, and they act as immunomodulators, signaling molecules, and inflammatory markers. When ferritin level exceeds 1000 µgL, the patient is categorized as having hyperferritinemia. Iron chelators such as deferiprone, deferirox, and deferoxamine are currently FDA approved to treat iron overload. The inflammation cascade and poor prognosis of COVID-19 may be attributed to high ferritin levels. Critically ill patients can benefit from deferasirox, an iron chelator administered orally at 20-40 mgkg once daily, as well as intravenous deferoxamine at 1000 mg initially followed by 500 mg every 4 to 12 h. It can be combined with monoclonal antibodies, antioxidants, corticosteroids, and lactoferrin to make iron chelation therapy effective for COVID-19 victims. In this article, we analyze the antiviral and antifibrotic activity of iron chelators, thereby promoting iron depletion therapy as a potentially innovative treatment strategy for COVID-19.
PubMed: 34924800
DOI: 10.1016/j.sjbs.2021.11.061 -
Life Sciences Dec 2019We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of...
AIMS
We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition.
MAIN METHODS
Mice from both wild-type (WT) and β-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month.
KEY FINDINGS
HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer's like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine.
SIGNIFICANCE
These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition.
Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Deferiprone; Dihydropyridines; Disease Models, Animal; Iron; Iron Chelating Agents; Iron Overload; Mice; Mice, Inbred C57BL; Neurotoxicity Syndromes; Nitrophenols; Organophosphorus Compounds; Thalassemia
PubMed: 31669736
DOI: 10.1016/j.lfs.2019.116878 -
Radiology Case Reports Nov 2022Superficial siderosis of the central nervous system is a chronic condition characterized by hemosiderin deposition in the brain and spinal cord. It's diagnosed by brain...
Superficial siderosis of the central nervous system is a chronic condition characterized by hemosiderin deposition in the brain and spinal cord. It's diagnosed by brain MRI. It can be caused by low-grade extravasation of blood into the subarachnoid space of the brain. There are 2 types of superficial siderosis cortical and infratentorial. Although asymptomatic in many cases; Cerebellar-predominant siderosis, a subtype of infratentorial, can affect hearing, gait, and even muscles. In this report, we present a case of a 51-year old female with complaints of hearing loss, unsteadiness in his lower limb, and spastic paresis. During MRI neuroimaging, we noticed findings of hypointensity areas within the brainstem and cerebellum, probably due to hemosiderin deposition. Based on the MRI findings, the patient was diagnosed with superficial siderosis. The patient was started on deferiprone and followed for the consecutive 18 months. Moderate improvement of the hearing loss and ataxia was noted while no change in muscle force. However, the repetitive MRI did not reveal any changes compared to the previous one.
PubMed: 36105843
DOI: 10.1016/j.radcr.2022.08.022 -
Platelets May 2020Thalassemia patients are susceptible to both iron overload and thromboembolism. Deferiprone is an iron chelator that shows an antiplatelet activity and thus may...
Thalassemia patients are susceptible to both iron overload and thromboembolism. Deferiprone is an iron chelator that shows an antiplatelet activity and thus may alleviate platelet hyperactivation in thalassemia. Therefore, this study aimed to characterize the inhibitory effects and mechanisms of deferiprone on normal human platelets. The results illustrated that deferiprone inhibited platelet aggregation at the iron chelating concentrations (0.08-0.25 mmol/l). Deferiprone inhibited human platelet aggregation stimulated by arachidonic acid and ADP more potently than epinephrine and collagen, with the IC of 0.24 mmol/l and 0.25 mmol/l . 3.36 mmol/l and 3.73 mmol/l, respectively. Interestingly, deferiprone significantly inhibited COX-1 activity, with the IC of 0.33 mmol/l, and slightly increased cAMP level at the high concentration of 4 mmol/l. Moreover, the results from molecular docking showed that deferiprone interacted closely with key residues in the peroxidase active site of COX-1. These results suggested that deferiprone possessed antiplatelet activity mainly through the inhibition of COX-1 activity.
Topics: Adenosine Diphosphate; Adolescent; Arachidonic Acid; Blood Platelets; Cyclic AMP; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Deferiprone; Humans; Inhibitory Concentration 50; Middle Aged; Molecular Docking Simulation; Platelet Aggregation; Platelet Aggregation Inhibitors; Young Adult
PubMed: 31366263
DOI: 10.1080/09537104.2019.1648782