Dopamine promotes cellular iron accumulation and oxidative stress responses in macrophages

Dichtl, Stefanie; Haschka, David; Nairz, Manfred; Seifert, Markus; Volani, Chiara; Lutz, Oliver; Weiß, Günter

doi:10.1016/j.bcp.2017.12.001

Cited by 60 publications

(59 citation statements)

References 54 publications

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“…Importantly, we found that RLS patients treated with dopaminergic drugs had significantly improved mitochondrial respiratory capacity compared with patients without treatment. Based on previous studies indicating that dopaminergic molecules such as neuromelanin affect iron homeostasis and the regulation of iron transporters and in agreement with our recent observation that dopamine directly increases cellular iron accumulation, these data would indicate that the beneficial effect of l ‐dopa or dopamine agonists is partially related to an increase in intracellular iron availability, thereby ameliorating mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome

et al. 2018

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Background Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. Methods We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age‐matched healthy controls focusing on iron metabolism using human monocytes as surrogates. Results Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. Conclusions Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. © 2018 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome

et al. 2018

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“…Iron is an essential component in neurotransmitter synthesis, where the metal is a co-factor of tyrosine hydroxylase, which converts tyrosine to DA and further to norepinephrine. The chemical compound, called catechol, may potentially bind iron [ 34 ]. An excess of iron may lead to a vast increase in the production of free radicals, which overwhelms the natural defensive mechanisms and causes damage at several cellular levels.…”

Section: Parkinson’smentioning

confidence: 99%

“…A study using murine bone marrow-derived macrophages showed that dopamine affected cellular iron homeostasis by increasing the uptake of non-transferrin bound iron. It resulted in intracellular oxidative stress responses and increased the transcriptional expression of stress response genes such as heme oxygenase-1 and the iron export protein ferroportin [ 34 ]. Also, the iron released from Neuromelanin (NM) increases oxidative stress in mitochondria, disrupting its function and reducing ATP-dependent proteasomal activity of 26S (the proteasome involved in the ubiquitin system) [ 36 ].…”

Section: Parkinson’smentioning

confidence: 99%

The Pathology of Parkinson’s Disease and Potential Benefit of Dietary Polyphenols

et al. 2020

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by a loss of dopaminergic neurons, leading to bradykinesia, rigidity, tremor at rest, and postural instability, as well as non-motor symptoms such as olfactory impairment, pain, autonomic dysfunction, impaired sleep, fatigue, and behavioral changes. The pathogenesis of PD is believed to involve oxidative stress, disruption to mitochondria, alterations to the protein α-synuclein, and neuroinflammatory processes. There is currently no cure for the disease. Polyphenols are secondary metabolites of plants, which have shown benefit in several experimental models of PD. Intake of polyphenols through diet is also associated with lower PD risk in humans. In this review, we provide an overview of the pathology of PD and the data supporting the potential neuroprotective capacity of increased polyphenols in the diet. Evidence suggests that the intake of dietary polyphenols may inhibit neurodegeneration and the progression of PD. Polyphenols appear to have a positive effect on the gut microbiome, which may decrease inflammation that contributes to the disease. Therefore, a diet rich in polyphenols may decrease the symptoms and increase quality of life in PD patients.

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“…Regarding AMPH, it did not cause significant changes in zebrafish social behavior, replicating what is known for rodents. PCA and clustering analysis suggest that in fact, both open tank and social interaction tests have sufficient resolution to identify distinct behavioral phenotypes related to schizophrenia in zebrafish models, specially following MK-801 exposure.Studies in rodent models report that increased dopamine release induced by AMPH promotes oxidative stress, probably due to increase monoamine metabolism(Dichtl et al, 2018;El-Tawil et al, 2011;Frey et al, 2006). All tested concentrations of AMPH increased TBARS, a well-established marker of lipid peroxidation, after 60 min, but not after 10 min of exposure, indicating a time-depend effect on the production of…”

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confidence: 84%

How do zebrafish respond to MK-801 and amphetamine? Relevance for assessing schizophrenia-relevant endophenotypes in alternative model organisms

Benvenutti

Gallas‐Lopes

Sachett

et al. 2020

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Background and Purpose: Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, loss of parvalbumin-positive GABAergic interneurons, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to investigate the effects of these drugs in zebrafish. Experimental Approach: Adult zebrafish were exposed to MK-801 (1, 5, and 10 uM) or amphetamine (0.625, 2.5, and 10 mg.L-1) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters relevant to schizophrenia were quantified in brain tissue. Key Results: MK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while increased lipid peroxidation in the brain. Conclusion and Implications: Key outcomes induced by MK-801 in rodents were replicated in zebrafish, which suggests this species is suitable as an alternative model animal to study psychotic disorders. More studies are necessary to further develop preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.

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Dopamine promotes cellular iron accumulation and oxidative stress responses in macrophages

Cited by 60 publications

References 54 publications

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome

The Pathology of Parkinson’s Disease and Potential Benefit of Dietary Polyphenols

How do zebrafish respond to MK-801 and amphetamine? Relevance for assessing schizophrenia-relevant endophenotypes in alternative model organisms

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