The glutathione system in Parkinson’s disease and its progression

Bjørklund, Geir; Peana, Massimiliano; Maes, Michaël; Dadar, Maryam; Severin, Beatrice

doi:10.1016/j.neubiorev.2020.10.004

Cited by 125 publications

(63 citation statements)

References 133 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, it was hypothesized that PFF-induced toxicity is, at least to a certain degree, mediated by glutathione depletion, which becomes critical when the cell accumulates an extensive amount of aggregates [ 86 ]. A strong association of the neurodegenerative diseases with the depletion of the GSH system has also been demonstrated in other studies [ 94 , 95 ]. Depletion of antioxidant systems in neurons, especially the glutathione system, leads to an increase in neuroinflammation and has an important role in the pathogenesis of neurodegenerative disorders [ 94 , 95 , 96 ].…”

Section: Glutathione Regulates Aging and Neurodegenerationsupporting

confidence: 72%

Glutathione in Brain Disorders and Aging

2022

View full text Add to dashboard Cite

Glutathione is a remarkably functional molecule with diverse features, which include being an antioxidant, a regulator of DNA synthesis and repair, a protector of thiol groups in proteins, a stabilizer of cell membranes, and a detoxifier of xenobiotics. Glutathione exists in two states—oxidized and reduced. Under normal physiological conditions of cellular homeostasis, glutathione remains primarily in its reduced form. However, many metabolic pathways involve oxidization of glutathione, resulting in an imbalance in cellular homeostasis. Impairment of glutathione function in the brain is linked to loss of neurons during the aging process or as the result of neurological diseases such as Huntington’s disease, Parkinson’s disease, stroke, and Alzheimer’s disease. The exact mechanisms through which glutathione regulates brain metabolism are not well understood. In this review, we will highlight the common signaling cascades that regulate glutathione in neurons and glia, its functions as a neuronal regulator in homeostasis and metabolism, and finally a mechanistic recapitulation of glutathione signaling. Together, these will put glutathione’s role in normal aging and neurological disorders development into perspective.

show abstract

Section: Glutathione Regulates Aging and Neurodegenerationsupporting

confidence: 72%

Glutathione in Brain Disorders and Aging

2022

View full text Add to dashboard Cite

show abstract

“…Thus, in neurodegenerative diseases under conditions of insufficient antioxidant systems [ 45 , 46 ], these reactions lead to an increase in the production of free radicals. Therefore, it can be assumed that a therapeutic effect is achieved due to a decrease in NQO2 activity [ 39 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Properties of Quinone Reductase 2 Inhibitor M-11, a 2-Mercaptobenzimidazole Derivative

Voronin

Kadnikov

Зайнуллина

et al. 2021

IJMS

View full text Add to dashboard Cite

The ability of NQO2 to increase the production of free radicals under enhanced generation of quinone derivatives of catecholamines is considered to be a component of neurodegenerative disease pathogenesis. The present study aimed to investigate the neuroprotective mechanisms of original NQO2 inhibitor M-11 (2-[2-(3-oxomorpholin-4-il)-ethylthio]-5-ethoxybenzimidazole hydrochloride) in a cellular damage model using NQO2 endogenous substrate adrenochrome (125 µM) and co-substrate BNAH (100 µM). The effects of M-11 (10–100 µM) on the reactive oxygen species (ROS) generation, apoptosis and lesion of nuclear DNA were evaluated using flow cytometry and single-cell gel electrophoresis assay (comet assay). Results were compared with S29434, the reference inhibitor of NQO2. It was found that treatment of HT-22 cells with M-11 results in a decline of ROS production triggered by incubation of cells with NQO2 substrate and co-substrate. Pre-incubation of HT-22 cells with compounds M-11 or S29434 results in a decrease of DNA damage and late apoptotic cell percentage reduction. The obtained results provide a rationale for further development of the M-11 compound as a potential neuroprotective agent.

show abstract

“…In contrast, both catalase and glutathione peroxidase activities were decreased in PD brains [ 33 ]. Alterations in the antioxidant defense system have already been described in peripheric tissues [ 34 , 35 ]. Thus, targeting mitochondrial oxidative stress with antioxidants that can specifically reduce over-stimulated mitochondrial ROS production in pathological processes may play a vital role in delaying disease pathogenesis and progression.…”

Section: Introductionmentioning

confidence: 99%

A mitochondria-targeted caffeic acid derivative reverts cellular and mitochondrial defects in human skin fibroblasts from male sporadic Parkinson's disease patients

et al. 2021

View full text Add to dashboard Cite

Parkinson's Disease (PD) is a neurodegenerative disorder affecting more than 10 million people worldwide. Currently, PD has no cure and no early diagnostics methods exist. Mitochondrial dysfunction is presented in the early stages of PD, and it is considered an important pathophysiology component. We have previously developed mitochondria-targeted hydroxycinnamic acid derivatives, presenting antioxidant and iron-chelating properties, and preventing oxidative stress in several biological models of disease. We have also demonstrated that skin fibroblasts from male sporadic PD patients (sPD) presented cellular and mitochondrial alterations, including increased oxidative stress, hyperpolarized and elongated mitochondria and decreased respiration and ATP levels. We also showed that forcing mitochondrial oxidative phosphorylation (OXPHOS) in sPD fibroblasts uncovers metabolic defects that were otherwise hidden. In this work, we tested the hypothesis that a lead mitochondria-targeted hydroxycinnamic acid derivative would revert the phenotype found in skin fibroblasts from sPD patients. Our results demonstrated that treating human skin fibroblasts from sPD patients with non-toxic concentrations of AntiOxCIN 4 restored mitochondrial membrane potential and mitochondrial fission, decreased autophagic flux, and enhanced cellular responses to stress by improving the cellular redox state and decreasing reactive oxygen species (ROS) levels. Besides, fibroblasts from sPD patients treated with AntiOxCIN 4 showed increased maximal respiration and metabolic activity, converting sPD fibroblasts physiologically more similar to their sex- and age-matched healthy controls. The positive compound effect was reinforced using a supervised machine learning model, confirming that AntiOxCIN 4 treatment converted treated fibroblasts from sPD patients closer to the phenotype of control fibroblasts. Our data points out a possible mechanism of AntiOxCIN 4 action contributing to a deeper understanding of how the use of mitochondria-targeted antioxidants based on a polyphenol scaffold can be used as potential drug candidates for delaying PD progression, validating the use of fibroblasts from sPD patients with more active OXPHOS as platforms for mitochondria-based drug development.

show abstract

The glutathione system in Parkinson’s disease and its progression

Cited by 125 publications

References 133 publications

Glutathione in Brain Disorders and Aging

Glutathione in Brain Disorders and Aging

Neuroprotective Properties of Quinone Reductase 2 Inhibitor M-11, a 2-Mercaptobenzimidazole Derivative

A mitochondria-targeted caffeic acid derivative reverts cellular and mitochondrial defects in human skin fibroblasts from male sporadic Parkinson's disease patients

Contact Info

Product

Resources

About