Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system

Benzi, G.; Moretti, Antonio

doi:10.1016/0891-5849(94)00244-e

Cited by 253 publications

(120 citation statements)

References 170 publications

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“…activity caused increased lipid peroxidation, in agreement with increasing evidence implicating C.O. inhibition and oxidative damage as neurodegenerative mechanisms in MCI and AD Benzi and Moretti, 1995;Blass et al, 2002;Mielke and Lyketsos, 2006;Reddy and Beal, 2005;Valla et al, 2001;Valla et al, 2006). The PCC may be a metabolically vulnerable brain region.…”

Section: Discussionsupporting

confidence: 65%

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Riha

Rojas

Colorado³

et al. 2008

Neurobiology of Learning and Memory

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The posterior cingulate cortex (PCC) is the brain region displaying the earliest sign of energy hypometabolism in patients with amnestic mild cognitive impairment (MCI) who develop Alzheimer's disease (AD). In particular, the activity of the mitochondrial respiratory enzyme cytochrome oxidase (C.O.) is selectively inhibited within the PCC in AD. The present study is the first experimental analysis designed to model in animals the localized cortical C.O. inhibition found as the earliest metabolic sign of early-stage AD in human neuroimaging studies. Rats were used to model local inhibition of C.O. by direct injection of the C.O. inhibitor sodium azide into the PCC. Learning and memory were examined in a spatial holeboard task and brains were analyzed using quantitative histochemical, morphological and biochemical techniques. Behavioral results showed that sodium azide-treated rats were impaired in their memory of the baited pattern in probe trials as compared to their training scores before treatment, without non-specific behavioral differences. Brain analyses showed that C.O. inhibition was specific to the PCC, and sodium azide increased lipid peroxidation, gliosis and neuron loss, and lead to a network functional disconnection between the PCC and interconnected hippocampal regions. It was concluded that impaired memory by local C.O. inhibition in the PCC may serve to model in animals a metabolic lesion similar to that found in patients with amnestic MCI and early-stage AD. This model may be useful as an in vivo testing platform to investigate neuroprotective strategies to prevent or reduce the amnestic effects produced by posterior cingulate energy hypometabolism.

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Section: Discussionsupporting

confidence: 65%

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Riha

Rojas

Colorado³

et al. 2008

Neurobiology of Learning and Memory

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“…The high activity of glycolysis to support ATP synthesis in this cell line may be responsible for the maintenance of ATP levels above a certain threshold when the cells were incubated in the presence of 0.5 mM glutamate. In the presence of high doses of glutamate (10 mM), the extensive alterations (Griffith and Meister, 1985), may result in impaired mitochondrial function (Heales et al, 1995), since all the complexes of the electron transport chain are reported to be susceptible to damage by oxygen free radicals, in vitro (Benzi and Moretti, 1995). The work of Nishikawa et al (1997) demonstrated that cytosolic GSH rather than intramitochondrial GSH, might be an important factor stabilizing the energy metabolism of mitochondria.…”

Section: Discussionmentioning

confidence: 97%

Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis

Pereira

Oliveira

2000

Neuroscience Research

143

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Glutamate toxicity on PC12 cells is mediated by oxidative stress as a consequence of the inhibition of a cystine uptake system with depletion of GSH. In this study we report that glutamate decreases PC12 cell viability, inhibiting the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). This decrease was prevented by the antioxidants vitamin E, idebenone and L-deprenyl, which were also shown to be effective in reducing the accumulation of reactive oxygen species (ROS) in cells exposed to glutamate, decreasing the fluorescence of 2%,7%-dichlorofluorescein (DCF). Incubation of PC12 cells with high glutamate concentrations induced mitochondrial dysfunction, leading to the loss of mitochondrial transmembrane potential, evaluated as a decrease in rhodamine 123 (Rh123) retention by mitochondria, and to the decrease of intracellular ATP levels. The mitochondrial dysfunction, induced by glutamate, can be involved in the observed increase of [Ca 2 + ] i . The elevation of [Ca 2 + ] i occurred after GSH depletion, suggesting that oxidative stress is involved in the disturbances of intracellular calcium homeostasis. In conclusion, our data indicate that glutamate, at concentrations which block cystine uptake in PC12 cells leading to GSH depletion and inducing oxidative stress, increases ROS accumulation and decreases cell survival by a mechanism involving mitochondrial dysfunction and impairment of Ca 2 + homeostasis.

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“…However, the impact of redox regulation in various cellular functions, especially neuronal function, has not been well described. There is evidence that ROS contribute to many pathological conditions, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease (47)(48)(49)(50)(51). Therefore, it is tempting to speculate that redox regulation of intracellular signaling molecules may contribute to these diseases.…”

Section: Fig 11mentioning

confidence: 99%

Superoxide-induced Stimulation of Protein Kinase C via Thiol Modification and Modulation of Zinc Content

Knapp

Klann

2000

Journal of Biological Chemistry

183

131

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We investigated the effects of mild oxidation on protein kinase C (PKC) using the xanthine/xanthine oxidase system of generating superoxide. Exposure of various PKC preparations to superoxide stimulated the autonomous activity of PKC. Similarly, thiol oxidation increased autonomous PKC activity, consistent with the notion that superoxide stimulates PKC via thiol oxidation. The superoxide-induced stimulation of PKC activity was partially reversed by reducing agents, suggesting that disulfide bond formation contributed to the oxidative stimulation of PKC. In addition, superoxide increased the autonomous activity of the ␣, ␤ II , ⑀, and PKC isoforms, all of which contain at least one cysteinerich region. Taken together, our observations suggested that superoxide interacts with PKC at the cysteine-rich region, zinc finger motif of the enzyme. Therefore, we examined the effects of superoxide on this region by testing the hypothesis that superoxide stimulates PKC by promoting the release of zinc from PKC. We found that a zinc chelator stimulated the autonomous activity of PKC and that superoxide induced zinc release from an PKC-enriched enzyme preparation. In addition, oxidized PKC contained significantly less zinc than reduced PKC. Finally, we have isolated a persistent, autonomously active PKC by DEAE-cellulose column chromatography from hippocampal slices incubated with superoxide. Taken together, these data suggest that superoxide stimulates autonomous PKC activity via thiol oxidation and release of zinc from cysteine-rich region of PKC.

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Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system

Cited by 253 publications

References 170 publications

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis

Superoxide-induced Stimulation of Protein Kinase C via Thiol Modification and Modulation of Zinc Content

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