Parkinson's disease

Segura‐Aguilar, Juan

doi:10.1016/b978-0-12-822120-4.00001-0

Cited by 2 publications

(3 citation statements)

References 817 publications

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“…The characteristic pathological features of substantia nigra in Parkinson’s patients comprise enhanced iron deposition and lipid peroxidation, as wells as defects in the transport system xc-. These attributes are congruent with the hallmarks of ferroptosis, which is currently receiving attention in various diseases [ 9 , 91 ]. Preventing the progressive loss of dopaminergic neurons by interfering with ferroptosis is a new approach to treatment [ 6 , 10 , 88 , 92 ].…”

Section: Neuroprotection Against Neurodegeneration Of Nigrostriatal S...mentioning

confidence: 76%

“…The discovery that the motor movements of Parkinson’s disease are related to the loss of the neuromelanin-containing dopaminergic neuron of the nigrostriatal system that generates a significant drop in the release of dopamine has implied that preclinical models based on exogenous neurotoxins such as 6-hydroxydopamine have played an important role in the investigation of this degenerative process and the development of potential therapies. There are two sources of oxidative stress generation in dopaminergic neurons, one being the oxidative deamination of dopamine catalyzed by the enzyme monoamine oxidase that generates ammonia and hydrogen peroxide [ 9 ], which in the presence of reduced iron generates hydroxyl radicals and therefore profuse oxidative stress within dopaminergic neurons. Another specific source of oxidative stress within dopaminergic neurons arises during the synthesis of neuromelanin which requires the oxidation of dopamine to three ortho-quinones (dopamine ortho-quinone, aminochrome, and 5,6-indolequinone).…”

Section: Clinical Studies To Develop Antioxidant Therapiesmentioning

confidence: 99%

“…The enzymes play a prominent role in the protection against reactive oxygen species (ROS). GPX4 is particularly active with phospholipid hydroperoxides and appears to play an essential function in preventing ferroptosis [ 9 , 91 ].…”

Section: Neuroprotection Against Neurodegeneration Of Nigrostriatal S...mentioning

confidence: 99%

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A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

Segura‐Aguilar

Mannervik

2023

Antioxidants

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Investigations of the effect of antioxidants on idiopathic Parkinson’s disease have been unsuccessful because the preclinical models used to propose these clinical studies do not accurately represent the neurodegenerative process of the disease. Treatment with certain exogenous neurotoxins induces massive and extremely rapid degeneration; for example, MPTP causes severe Parkinsonism in just three days, while the degenerative process of idiopathic Parkinson´s disease proceeds over many years. The endogenous neurotoxin aminochrome seems to be a good alternative target since it is formed in the nigrostriatal system neurons where the degenerative process occurs. Aminochrome induces all the mechanisms reported to be involved in the degenerative processes of idiopathic Parkinson’s disease. The presence of neuromelanin-containing dopaminergic neurons in the postmortem brain of healthy elderly people suggests that neuromelanin synthesis is a normal and harmless process despite the fact that it requires oxidation of dopamine to three ortho-quinones that are potentially toxic, especially aminochrome. The apparent contradiction that neuromelanin synthesis is harmless, despite its formation via neurotoxic ortho-quinones, can be explained by the protective roles of DT-diaphorase and glutathione transferase GSTM2-2 as well as the neuroprotective role of astrocytes secreting exosomes loaded with GSTM2-2. Increasing the expression of DT-diaphorase and GSTM2-2 may be a therapeutic goal to prevent the degeneration of new neuromelanin-containing dopaminergic neurons. Several phytochemicals that induce DT-diaphorase have been discovered and, therefore, an interesting question is whether these phytochemical KEAP1/NRF2 activators can inhibit or decrease aminochrome-induced neurotoxicity.

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Section: Neuroprotection Against Neurodegeneration Of Nigrostriatal S...mentioning

confidence: 76%

Section: Clinical Studies To Develop Antioxidant Therapiesmentioning

confidence: 99%

See 1 more Smart Citation

A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

Segura‐Aguilar

Mannervik

2023

Antioxidants

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On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo

et al. 2017

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Dopamine oxidation in the pathway leading to neuromelanin formation generates the ortho-quinone aminochrome, which is potentially neurotoxic but normally rapidly converted by DT-diaphorase to nontoxic leukoaminochrome. However, when administered exogenously into rat striatum, aminochrome is able to produce damage to dopaminergic neurons. Because of a recent report that substantia nigra pars compacta (SNpc) tyrosine hydroxylase (T-OH) levels were unaltered by aminochrome when there was cell shrinkage of dopaminergic neurons along with a reduction in striatal dopamine release, the following study was conducted to more accurately determine the role of DT-diaphorase in aminochrome neurotoxicity. In this study, a low dose of aminochrome (0.8 nmol) with or without the DT-diaphorase inhibitor dicoumarol (0.2 nmol) was injected into the left striatum of rats. Intrastriatal 6-hydroxydopamine (6-OHDA, 32 nmol) was used as a positive neurotoxin control in other rats. Two weeks later, there was significant loss in numbers of T-OH immunoreactive fibers in SNpc, also a loss in cell density in SNpc, and prominent apomorphine (0.5 mg/kg sc)-induced contralateral rotations in rats that had been treated with aminochrome, with aminochrome/dicoumarol, or with 6-OHDA. Findings demonstrate that neurotoxic aminochrome is able to exert neurotoxicity only when DT-diaphorase is suppressed-implying that DT-diaphorase is vital in normally suppressing toxicity of in vivo aminochrome, generated in the pathway towards neuromelanin formation.

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Parkinson's disease

Cited by 2 publications

References 817 publications

A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo

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