Is Chelation Therapy a Potential Treatment for Parkinson’s Disease?

Ward, Roberta J.; Dexter, David T.; Martín-Bastida, Antonio; Crichton, Robert R.

doi:10.3390/ijms22073338

Cited by 19 publications

(11 citation statements)

References 122 publications

(175 reference statements)

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“…There are several ongoing clinical trials testing iron chelation as a treatment for PD 14,58 based on the premise that iron accumulation may be related etiologically to PD and/or propel disease progression. These trials have targeted new PD patients with the assumption that iron accumulation in the SN occurs before symptom onset and levodopa treatment.…”

Section: Relevance and Limitations Of Our Findingsmentioning

confidence: 99%

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage

Wang

Sica

et al. 2022

Movement Disorders

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A BS TRACT: Background: Higher nigral iron has been reported in Parkinson's disease (PD).Objective: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. Methods: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PD DN ) and 87 drug-treated (PD DT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PD DN and PD DT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. Results: Compared to controls, PD DN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PD DT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PD DN . Iron in the nigra increased with disease duration (PDE > PD DN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). Conclusion: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation.

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Section: Relevance and Limitations Of Our Findingsmentioning

confidence: 99%

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage

Wang

Sica

et al. 2022

Movement Disorders

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“…DFO action can also be coupled with antioxidants to counteract neurotoxicity in dopaminergic neurons of the substantia nigra, reducing oxidative stress and cellular damage [ 54 ]. Clinical trials on an orally active form of the iron chelator deferiprone (DFP) showed decreases in substantia nigra iron content resulting in improved Unified Parkinson’s Disease Rating Scale (UPDRS) scores [ 55 ]. GRM2 modulators have risen in interest, given that allosteric modulators of G-protein-coupled receptors (GPCRs) appear to provide a new strategy to develop novel treatments in neurodegenerative diseases in general and PD in particular [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

A Hybrid Machine Learning and Network Analysis Approach Reveals Two Parkinson’s Disease Subtypes from 115 RNA-Seq Post-Mortem Brain Samples

Termine

Fabrizio

Strafella

et al. 2022

IJMS

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Precision medicine emphasizes fine-grained diagnostics, taking individual variability into account to enhance treatment effectiveness. Parkinson’s disease (PD) heterogeneity among individuals proves the existence of disease subtypes, so subgrouping patients is vital for better understanding disease mechanisms and designing precise treatment. The purpose of this study was to identify PD subtypes using RNA-Seq data in a combined pipeline including unsupervised machine learning, bioinformatics, and network analysis. Two hundred and ten post mortem brain RNA-Seq samples from PD (n = 115) and normal controls (NCs, n = 95) were obtained with systematic data retrieval following PRISMA statements and a fully data-driven clustering pipeline was performed to identify PD subtypes. Bioinformatics and network analyses were performed to characterize the disease mechanisms of the identified PD subtypes and to identify target genes for drug repurposing. Two PD clusters were identified and 42 DEGs were found (p adjusted ≤ 0.01). PD clusters had significantly different gene network structures (p < 0.0001) and phenotype-specific disease mechanisms, highlighting the differential involvement of the Wnt/β-catenin pathway regulating adult neurogenesis. NEUROD1 was identified as a key regulator of gene networks and ISX9 and PD98059 were identified as NEUROD1-interacting compounds with disease-modifying potential, reducing the effects of dopaminergic neurodegeneration. This hybrid data analysis approach could enable precision medicine applications by providing insights for the identification and characterization of pathological subtypes. This workflow has proven useful on PD brain RNA-Seq, but its application to other neurodegenerative diseases is encouraged.

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“…In recent years, there has been a growing interest in the development of multi-target drugs that combine iron-chelation and anti-inflammatory properties. Recent studies of patients with Parkinson's disease treated with deferiprone showed decreases in substantia nigra iron content and improved scores on the Parkinson's Disease Rating Scale (Ward et al, 2021). Using a septic animal model, Fokam et al (2020) reported that the iron-chelator DIBI could be a promising anti-inflammatory treatment, either alone or combined with antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy

et al. 2022

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Encephalopathy is a frequent and lethal consequence of sepsis. Recently, a growing body of evidence has provided important insights into the role of iron dyshomeostasis in the context of inflammation. The molecular mechanisms underlying iron dyshomeostasis and its relationship with macrophage phenotypes are largely unknown. Here, we aimed to characterize the changes in iron-transporter and storage proteins and the microglia phenotype that occur during the course of sepsis, as well as their relationship with sepsis-induced encephalopathy. We used a cecal ligation and puncture (CLP) murine model that closely resembles sepsis-induced encephalopathy. Rats were subjected to CLP or sham laparotomy, then were neurologically assessed at 6 h, 24 h, and 3 days after sepsis induction. The serum and brain were collected for subsequent biochemical, histological, and immunohistochemical assessment. Here, an iron excess was observed at time points that followed the pro-inflammatory macrophage polarization in CLP-induced encephalopathy. Our results revealed that the upregulation of non-transferrin-bound iron uptake (NTBI) and ferritin reduction appeared to be partially responsible for the excess free iron detected within the brain tissues. We further demonstrated that the microglia were shifted toward the pro-inflammatory phenotype, leading to persistent neuro-inflammation and neuronal damage after CLP. Taken together, these findings led us to conclude that sepsis increased the susceptibility of the brain to the iron burden via the upregulation of NTBI and the reduction of ferritin, which was concomitantly and correlatively associated with dominance of pro-inflammatory microglia and could explain the neurological dysfunction observed during sepsis.

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Is Chelation Therapy a Potential Treatment for Parkinson’s Disease?

Cited by 19 publications

References 122 publications

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage

A Hybrid Machine Learning and Network Analysis Approach Reveals Two Parkinson’s Disease Subtypes from 115 RNA-Seq Post-Mortem Brain Samples

Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy

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