Brain Oxidative Stress in Animal Models of Accelerated Aging and the Age-related Neurodegenerative Disorders, Alzheimers Disease and Huntingtons Disease

Butterfield, D. Allan; Howard, Beverly J.; LaFontaine, Michael

doi:10.2174/0929867013373048

Cited by 123 publications

(56 citation statements)

References 165 publications

(248 reference statements)

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“…With age the production of oxidants increases, and there is a decrease in antioxidant protection, and=or the damage oxidants inflict begins to exceed the cell's ability to repair the resulting damage (Butterfield et al, 2001). When the production of oxidants exceeds antioxidant defenses, the condition is known as oxidative stress, and this has is known to play a substantial role in accelerated aging, and in the damage seen after TBI (Ansari et al, 2008a(Ansari et al, , 2008b.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Mitochondrial Changes after Traumatic Brain Injury

Gilmer

Ansari

Roberts

et al. 2010

Journal of Neurotrauma

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Mitochondrial dysfunction is known to occur following traumatic brain injury (TBI) and has been well characterized. This study assessed possible age-related changes in the cortical mitochondrial bioenergetics following TBI. Three hours following a moderate TBI, tissue from the ipsilateral hemisphere (site of impact and penumbra) and the corresponding contralateral region were harvested from young (3-to 5-month-old) and aged (22-to 24-month-old) Fischer 344 rats. Synaptic and extrasynaptic mitochondria were isolated using a Ficoll gradient, and several bioenergetic parameters were examined using a Clark-type electrode. Injury-related respiration deficits were observed in both young and aged rats. Synaptic mitochondria showed an age-related decline in the rate of ATP production, and a decline in respiratory control ratios (RCR), which were not apparent in the extrasynaptic fraction. Following respiration analysis, mitochondrial samples were probed for oxidative damage (3-nitrotyrosine [3-NT], 4-hydroxynonenal [4-HNE], and protein carbonyls [PC]). All markers of oxidative damage were elevated with injury and age in the synaptic fraction, but only with injury in the extrasynaptic fraction. Synaptic mitochondria displayed the highest levels of oxidative damage and may contribute to the synaptic bioenergetic deficits seen following injury. Data indicate that cortical synaptic mitochondria appear to have an increased susceptibility to perturbation with age, suggesting that the increased mitochondrial dysfunction observed following injury may impede recovery in aged animals.

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Section: Discussionmentioning

confidence: 99%

Age-Related Mitochondrial Changes after Traumatic Brain Injury

Gilmer

Ansari

Roberts

et al. 2010

Journal of Neurotrauma

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“…Oxidative damage to biological macromolecules has been implicated in cancer, inflammation, cardiovascular, and neurodegenerative diseases and aging (2)(3)(4)(5)(6)(7). Eukaryote cells, which are exposed to reactive oxygen species from both intrinsic and extrinsic sources, have evolved multiple mechanisms to neutralize reactive molecules and minimize oxidative damage.…”

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confidence: 99%

Crystal Structure of the Kelch Domain of Human Keap1

Zhang

Hannink

et al. 2004

Journal of Biological Chemistry

203

181

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Keap1 is a substrate adaptor protein for an ubiquitin ligase complex that targets the Nrf2 transcription factor for degradation. Keap1 binds Nrf2 through its C-terminal Kelch domain, which contains six copies of the evolutionarily conserved kelch repeat sequence motif. The structure of the Kelch domain from human Keap1 has been determined by x-ray crystallography to a resolution of 1.85 Å. The Kelch domain forms a 6-bladed ␤-propeller structure, with residues at the C terminus forming the first strand in the first blade. Key structural roles have been identified for the highly conserved glycine, tyrosine, and tryptophan residues that define the kelch repeat sequence motif. In addition, we show that substitution of a single amino acid located within a loop that extends out from the bottom of the ␤-propeller structure abolishes binding of Nrf2. The structure of the Kelch domain of Keap1 represents a high quality model for the superfamily of eukaryotic kelch repeat proteins and provides insight into how disease-causing mutations perturb the structural integrity of the Kelch domain.

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“…These neurons were also deficient in the AO cysteine. Another report demonstrates a role for free radicals in OS involving HD [147]. Other findings support a role for free radicals in the onset and progression of the disease [148].…”

Section: Huntington’s Disease (Hd)mentioning

confidence: 91%

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

Kovacic

Somanathan²

2012

Current Neuropharmacology

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Much attention has been devoted to neurodegenerative diseases involving redox processes. This review comprises an update involving redox processes reported in the considerable literature in recent years. The mechanism involves reactive oxygen species and oxidative stress, usually in the brain. There are many examples including Parkinson’s, Huntington’s, Alzheimer’s, prions, Down’s syndrome, ataxia, multiple sclerosis, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis, schizophrenia, and Tardive Dyskinesia. Evidence indicates a protective role for antioxidants, which may have clinical implications. A multifaceted approach to mode of action appears reasonable.

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Brain Oxidative Stress in Animal Models of Accelerated Aging and the Age-related Neurodegenerative Disorders, Alzheimers Disease and Huntingtons Disease

Cited by 123 publications

References 165 publications

Age-Related Mitochondrial Changes after Traumatic Brain Injury

Age-Related Mitochondrial Changes after Traumatic Brain Injury

Crystal Structure of the Kelch Domain of Human Keap1

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

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