Manganese catalyzed auto-oxidation of dopamine to 6-Hydroxydopamine in vitro

Garner, Charles D.; Nachtman, J. P.

doi:10.1016/0009-2797(89)90120-8

Cited by 25 publications

(17 citation statements)

References 10 publications

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“…Dopamine itself is a strong oxidant that can undergo an auto-oxidation process to produce highly damaging intermediates, which makes a strong argument for the vulnerability of DA-specific brain areas to toxins and other oxidants 59 . Mn has been shown to catalyse dopamine oxidation 60 , while Fe has been shown to specifically bind neuromelanin found in DAergic neurons 61 . Thus, the pdr-1 KO; fpn-1.1 OVR animals may show improvement in the DA-dependent BSR due to the lower bioavailability of Mn, Fe and Cu that would otherwise participate in directly enhancing DA oxidation and/or indirectly producing damaging free radicals in an already susceptible cell type.…”

Section: Discussionmentioning

confidence: 99%

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

et al. 2015

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Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson's disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

et al. 2015

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“…This neurotoxin can be generated within the brain by nonenzymatic reaction of dopamine, hydrogen peroxide, and free iron [67–69]. Auto-oxidation of dopamine by nitrite ions or manganese can also generate 6-OHDA [70, 71]. Oxidative damage via hydrogen peroxide and derived •OH are associated with the neurotoxic mechanism by 6-OHDA [64].…”

Section: 6-ohda Model and Oxidative Damage In Nigrostriatal Neuronsmentioning

confidence: 99%

Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

Fujita

Nakabeppu

Нода

2011

Parkinson's Disease

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Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD.

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“…The substantia nigra, with its large stores of iron, may provide the catalyst for 6-OHDA production (83,92). Furthermore, 6-OHDA could be generated in this environment in the presence of DA by either free nitrite ions or manganese (93,94). 6-OHDA generates an increase in the production of hydrogen peroxide and free radicals, including the superoxide ion and hydroxyl radical (95,96).…”

Section: Dopamine Dopamine Transporter and Parkinson's Diseasementioning

confidence: 99%

TheCaenorhabditis elegansDopaminergic System: Opportunities for Insights into Dopamine Transport and Neurodegeneration

Nass

Blakely

2003

Annu. Rev. Pharmacol. Toxicol.

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The neurotransmitter dopamine (DA) plays a central role in the coordination of movement, attention, and the recognition of reward. Loss of DA from the basal ganglia, as a consequence of degeneration of neurons in the substantia nigra, triggers postural instability and Parkinson's disease (PD). DA transporters (DATs) regulate synaptic DA availability and provide a conduit for the uptake of DA mimetic neurotoxins, which can be used to evoke neuronal death and Parkinson-like syndrome. Recently, we have explored the sensitivity of DA neurons in the nematode Caenorhabditis elegans to the Parkinsonian-inducing neurotoxin 6-hydroxydopamine (6-OHDA) and found striking similarities, including DAT dependence, to neurodegeneration observed in mammalian models. In this review, we present our findings in the context of molecular and behavioral dimensions of DA signaling in C. elegans with an eye toward opportunities for uncovering DAT mutants, DAT regulators, and components of toxin-mediated cell death.

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Manganese catalyzed auto-oxidation of dopamine to 6-Hydroxydopamine in vitro

Cited by 25 publications

References 10 publications

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

TheCaenorhabditis elegansDopaminergic System: Opportunities for Insights into Dopamine Transport and Neurodegeneration

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