Oxidative Stress in Alzheimer’s Disease: Why Did Antioxidant Therapy Fail?

Persson, Torbjörn; Popescu, Bogdan Ovidiu; Cedazo-Minguez, Ángel

doi:10.1155/2014/427318

Cited by 261 publications

(221 citation statements)

References 112 publications

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“…Does 'redox' provide a platform for therapeutic intervention? Although preclinical data suggest that treatment with free radical quenchers can improve ER-stress-dependent atrophy (Back et al, 2009;Malhotra et al, 2008), the translation of such therapies into the clinic is challenging (see, for example, Persson et al, 2014). One of the associated problems is illustrated by the dual role that NRF2 has in cancer; by increasing the endogenous antioxidant capacities, NRF2-inducing treatments lower the sensitivity to carcinogens but, at the same time, increase the risk of resistance against anti-cancer chemotherapy (Ma, 2013).…”

Section: Discussionmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

153

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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Section: Discussionmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

153

137

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“…Moreover, a recent study confirmed the beneficial effect of Se on neurotoxicity induced by aluminium chloride (AlCl 3 ). Lakshmi et al showed that this micronutrition effectively prevented the harmful effects of this toxin in behaviour and biochemical changes, and a decrease in brain oxidative damages, neuronal inflammation and improvement of the working and attention memory were observed [134].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Selenium in the therapy of neurological diseases. Where is it going?

Dominiak¹,

Wilkaniec²,

Wroczyński³

et al. 2015

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Selenium ( 34 Se), an antioxidant trace element, is an important regulator of brain function. These beneficial properties that Se possesses are attributed to its ability to be incorporated into selenoproteins as an amino acid. Several selenoproteins are expressed in the brain, in which some of them, e.g. glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) or selenoprotein P (SelP), are strongly involved in antioxidant defence and in maintaining intercellular reducing conditions. Since increased oxidative stress has been implicated in neurological disorders, including Parkinson's disease, Alzheimer's disease, stroke, epilepsy and others, a growing body of evidence suggests that Se depletion followed by decreased activity of Se-dependent enzymes may be important factors connected with those pathologies. Undoubtedly, the remarkable progress that has been made in understanding the biological function of Se in the brain has opened up new potential possibilities for the treatment of neurological diseases by using Se as a potential drug. However, further research in the search for optimal Se donors is necessary in order to achieve an effective and safe therapeutic income.

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“…Increased amounts of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde which are products of lipid peroxidation [18] have been found on post-mortem analysis of human brains from aceruloplasminemia patients [19]. Protein carbonyl groups and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxdG) as markers of oxidative damage to proteins and DNA can be detected in tissue of various neurodegenerative disorders including AD [20][21][22][23]. Also, depletion of endogenous antioxidants such as glutathione has been documented in the substantia nigra of PD patients further supporting the role of oxidative stress in neurodegeneration [24].…”

Section: Causes and Consequences Of Cerebral Iron Accumulationmentioning

confidence: 99%

Iron chelation in the treatment of neurodegenerative diseases

Dušek

Schneider

Aaseth

2016

Journal of Trace Elements in Medicine and Biology

104

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a b s t r a c tDisturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

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Oxidative Stress in Alzheimer’s Disease: Why Did Antioxidant Therapy Fail?

Cited by 261 publications

References 112 publications

Redox controls UPR to control redox

Redox controls UPR to control redox

Selenium in the therapy of neurological diseases. Where is it going?

Iron chelation in the treatment of neurodegenerative diseases

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