Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases

Chiurchiù, Valerio; Orlacchio, Antonio; Maccarrone, Mauro

doi:10.1155/2016/7909380

Cited by 122 publications

(88 citation statements)

References 106 publications

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“…The brain is particularly vulnerable to oxidative stress due to its high oxygen consumption and high production of reactive oxygen and nitrogen species. Accumulating evidence has demonstrated that oxidative stress plays an important role in excitotoxicity, axonal damage and neuronal death (Chiurchiu et al, 2015), and is involved in the onset and progression of several neurodegenerative diseases, such as AD, PD, HD, and amyotrophic lateral sclerosis (ALS) (Radi et al, 2014; Cobb and Cole, 2015). Oxidative stress also plays an important role in TD-induced brain damage (Liu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Wang

Frank

et al. 2017

Toxicology and Applied Pharmacology

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Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Wang

Frank

et al. 2017

Toxicology and Applied Pharmacology

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“…The brain is particularly susceptible to oxidative stress for many reasons. First and foremost, although it comprises only 2% of total body weight the brain consumes 20% of the body’s total oxygen supply, with a significant portion of that oxygen subsequently being converted into reactive oxygen species (ROS) (7, 8, 9). Secondly, in the brain there are specific neurochemical reactions, like dopamine oxidation, which create large amounts of reactive oxygen or nitrogen species (ROS, RNS).…”

Section: Oxidative Stressmentioning

confidence: 99%

“…Thirdly, the brain has large amounts of lipids (e.g., myelin), which are sensitive to oxidative stress. Lastly, with aging there is increased deposition of metal ions in the brain, which are catalysts in the production of ROS and RNS (9, 10). …”

Section: Oxidative Stressmentioning

confidence: 99%

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

112

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Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants. Urate, the main antioxidant found in plasma as well as the end product of purine metabolism in humans, has emerged as a promising potential neuroprotectant with advantages that distinguish it from previously tested antioxidant agents. Uniquely, higher urate levels in plasma or cerebrospinal fluid (CSF) have been linked to both a lower risk of developing PD and to a slower rate of its subsequent progression in numerous large prospective epidemiological and clinical cohorts. Laboratory evidence that urate confers neuroprotection in cellular and animal models of PD, possibly via the Nrf2 antioxidant response pathway, further strengthened its candidacy for rapid clinical translation. An early phase trial of the urate precursor inosine demonstrated its capacity to safely produce well tolerated, long-term elevation of plasma and CSF urate in early PD, supporting a phase 3 trial now underway to determine whether oral inosine dosed to elevate urate to concentrations predictive of favorable prognosis in PD slows clinical decline in people recently diagnosed, dopamine transporter-deficient PD.

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“…Although the clinical manifestations differ for these disorders, a common denominator in their pathology is the induction of oxidative stress [7, 8]. For the past several decades, evidence has accumulated supporting oxidative stress as an underlying common denominator of brain injury and neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 99%

NADPH oxidase in brain injury and neurodegenerative disorders

Merry

Wang

Zhang

et al. 2017

Mol Neurodegeneration

342

309

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Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.

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Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases

Cited by 122 publications

References 106 publications

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Targeting urate to reduce oxidative stress in Parkinson disease

NADPH oxidase in brain injury and neurodegenerative disorders

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