Association of freezing of gait with nigral iron accumulation in patients with Parkinson's disease.
J Neurol Sci. 2017 Nov 15;382:61-65. doi: 10.1016/j.jns.2017.09.033. Epub 2017 Sep 23.
Naduthota RM1, Honnedevasthana AA2, Lenka A3, Saini J4, Geethanath S2, Bharath RD4, Christopher R5, Yadav R1, Gupta AK4, Pal PK6.
Abstract
BACKGROUND AND PURPOSE:
The objective of this work was to investigate whether patients with and without freezing of gait (FOG) in Parkinson's disease (PD) have differences in iron accumulation in substantia nigra using R2* relaxometry.
MATERIALS AND METHODS:
This study included seventeen PD patients with FOG [FOG (+)], equal number of age and gender matched patients without FOG [FOG (-)] and 34 healthy controls (HC). T2* images were obtained from a 3-Tesla MRI system using multi-echo sequence. R2* values
were extracted from Substantia Nigra (SN) and red nucleus and were compared among the three groups and correlated with clinical findings.
RESULTS:
R2* values were increased in PD group as a whole compared to HC in rostral and caudal segments of Substantia Nigra pars compacta (SNc) and in Substantia Nigra pars reticulata (SNr) but not in red nucleus. Within PD subgroups, FOG (+) group had increased
iron accumulation in SNc compared to FOG (-) and HC. FOG score positively correlated with R2* values in the caudal region of SNc in FOG (+) group.
CONCLUSIONS:
Our study reveals higher nigral iron content in FOG (+) compared to FOG (-) and HCs. In addition, we observed positive correlation of FOG score with iron accumulation in SNc. Results of this study emphasize possible role of higher nigral iron content in
the pathogenesis of FOG in PD.
Copyright © 2017 Elsevier B.V. All rights reserved.

KEYWORDS:
Freezing; Gait; Parkinson's disease; R2* relaxometry
PMID: 29111022 DOI: 10.1016/j.jns.2017.09.033

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Mechanism underlying the effectiveness of deferiprone in alleviating Parkinson's disease symptoms.
Sun Y, Pham AN, Waite TD.
ACS Chem Neurosci. 2018 Jan 30. doi: 10.1021/acschemneuro.7b00478.

Abstract
Elevation in iron content as well as severe depletion of dopamine (DA) as a result of iron-induced loss of dopaminergic neurons has been recognized to accompany the progression of Parkinson's disease (PD). To better understand the mechanism of the
mitigating effect of the iron chelator deferiprone (DFP) on PD, the interplay between iron and DFP was investigated both in the absence and presence of DA. The results show that DFP was extremely efficient in scavenging both aqueous iron and iron that
was loosely bound to DA with the entrapment of iron in Fe-DFP complexed form critical to halting the iron catalyzed degradation of DA and associated generation of toxic metabolites. The DFP related scavenging of dopamine semiquinone ( ) and superoxide ( )
may also contribute to its positive effects in the treatment of PD.

PMID: 29381045 DOI: 10.1021/acschemneuro.7b00478

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The effect of vitamin C and iron on dopamine-mediated free radical generation: implications to Parkinson's disease.
Sun Y1, Pham AN1, Waite TD1.
Dalton Trans. 2018 Feb 6.
doi: 10.1039/c7dt04373b.

Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. The oxidative stress and DA derived quinones have been proposed to be closely related to the progression of PD. To examine the possibility of the application of
ascorbate (Asc) as a therapeutic strategy in PD, the effect of Asc on the fate of iron both in the absence and presence of DA was investigated. The results of this study indicate that, in the absence of iron, the presence of high concentrations of Asc is
of great benefit in view of the alleviation in oxidative stress and formation of DA derived quinones by quenching radicals, such as O2˙- and DA˙-. As a well-known reductant, the presence of high concentrations of Asc in iron enriched solution results
in elevation in the concentration of active Fe(ii), which poses a potential threat to health as a result of inefficient oxygenation. While a competition exists between Asc and DA, the higher affinity of DA towards iron coupled with the formation of the
more stable FeIIIDA2 complex renders Asc unlikely to reduce the DA bound iron. The results of this study suggest that while the application of Asc alone may aggravate the progression of PD in view of the possible peroxidation of Asc bound Fe(ii), a
combination therapy of Asc and strong clinically used iron chelator would appear to be a promising direction for the treatment of PD as a result of the enhanced iron chelation and attenuation in oxidative stress and toxicity induced by DA derived
quinones.

PMID: 29406547 DOI: 10.1039/c7dt04373b

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Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice.
Xu SF1, Zhang YH1, Wang S1, Pang ZQ1, Fan YG1, Li JY2, Wang ZY3, Guo C4.
Redox Biol. 2018 Dec 21;21:101090. doi: 10.1016/j.redox.2018.101090.
Abstract
Brain iron accumulation is common in patients with Parkinson's disease (PD). Iron chelators have been investigated for their ability to prevent neurodegenerative diseases with features of iron overload. Given the non-trivial side effects of classical
iron chelators, lactoferrin (Lf), a multifunctional iron-binding globular glycoprotein, was screened to identify novel neuroprotective pathways against dopaminergic neuronal impairment. We found that Lf substantially ameliorated PD-like motor dysfunction
in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. We further showed that Lf could alleviate MPTP-triggered apoptosis of DA neurons, neuroinflammation, and histological alterations. As expected, we also found
that Lf suppressed MPTP-induced excessive iron accumulation and the upregulation of divalent metal transporter (DMT1) and transferrin receptor (TFR), which is the main intracellular iron regulation protein, and subsequently improved the activity of
several antioxidant enzymes. We probed further and determined that the neuroprotection provided by Lf was involved in the upregulated levels of brain-derived neurotrophic factor (BDNF), hypoxia-inducible factor 1α (HIF-1α) and its downstream protein,
accompanied by the activation of extracellular regulated protein kinases (ERK) and cAMP response element binding protein (CREB), as well as decreased phosphorylation of c-Jun N-terminal kinase (JNK) and mitogen activated protein kinase (MAPK)/P38 kinase
in vitro and in vivo. Our findings suggest that Lf may be an alternative safe drug in ameliorating MPTP-induced brain abnormalities and movement disorder.

KEYWORDS:
Iron chelators; Lactoferrin; Motor dysfunction; Parkinson's disease

PMID: 30593976 DOI: 10.1016/j.redox.2018.101090
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Time-Specific Pattern of Iron Deposition in Different Regions in Parkinson's Disease Measured by Quantitative Susceptibility Mapping
Xiaodi Fu 1, Wenbin Deng 1, Xiangqin Cui 1, Xiao Zhou 2, Weizheng Song 3, Mengqiu Pan 4, Xiao Chi 1, Jinghui Xu 5, Ying Jiang 5, Qun Wang 1, Yunqi Xu Front Neurol
. 2021 Aug 4;12:631210. doi: 10.3389/fneur.2021.631210. eCollection 2021.
PMID: 34421781 PMCID: PMC8371047 DOI: 10.3389/fneur.2021.631210
Abstract
Studies have shown the spatial specificity of cranial iron deposition in different regions in Parkinson's disease (PD). However, the time-specific patterns of iron deposition are not yet clear. The purpose of this study was to investigate the time
pattern of iron variations and its clinical relevance in multiple gray matter nuclei in PD using quantitative susceptibility mapping (QSM). Thirty controls and 33 PD patients were enrolled, namely, 11 cases of early stage of PD (ESP) and 22 cases of
advanced stage of PD (ASP) according to the Hoehn-Yahr stages. The iron content in the subcortical nuclei covering substantia nigra (SN), red nucleus (RN), head of the caudate nucleus (CN), globus pallidus (GP), and putamen (PT) was measured using QSM,
and the clinical symptoms of PD were evaluated by various rating scales. The QSM values in SN, RN, GP, and PT significantly increased in PD patients compared with the controls. Further subgroup comparison with the controls indicated that the iron content
in SN and GP (paleostriatum) gradually elevated in the whole disease duration and was related to clinical features. While the iron content in RN and PT (neostriatum) only elevated significantly in ESP patients, further iron deposition was not obvious in
ASP patients. Our study confirmed that QSM could be used as a disease biomarker and could be suitable for longitudinal monitoring. However, considering the temporal characteristics of iron deposition in neostriatum, iron deposition in the neostriatum
should be paid more attention in the early stage of the disease, even in the preclinical stage, in future research.

Keywords: hoehn-yahr stage; iron deposition; parkinson's disease; quantitative susceptibility mapping; unified parkinson's disease rating scale.

Copyright © 2021 Fu, Deng, Cui, Zhou, Song, Pan, Chi, Xu, Jiang, Wang and Xu.


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Review Mol Neurobiol. 2021 Aug 23. doi: 10.1007/s12035-021-02516-5.
Toxic Feedback Loop Involving Iron, Reactive Oxygen Species, α-Synuclein and Neuromelanin in Parkinson's Disease and Intervention with Turmeric
Zuné Jansen van Rensburg 1, Shameemah Abrahams 1 2, Soraya Bardien 3 4, Colin Kenyon 5 6 7
PMID: 34426907 DOI: 10.1007/s12035-021-02516-5
Abstract
Parkinson's disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing
dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in
neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase
each other's levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin's binding affinity is
affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD
pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain 'nutraceuticals' may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant
and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.

Keywords: Alpha-synuclein; Iron; Neuromelanin; Parkinson’s disease; Reactive oxygen species; Toxic feedback loop.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.


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