H2O2-mediated modulation of cytosolic signaling and organelle function in rat hippocampus

Gerich, Florian; Funke, Frank; Hildebrandt, Belinda; Faßhauer, M; Müller, Michael

doi:10.1007/s00424-009-0672-0

Cited by 57 publications

(56 citation statements)

References 61 publications

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“…Inhibition of ROS production by vitamin E and Trolox led to a decrease in the Ca 2+ response in astrocytes after activation with ATP, which was dependent on intracellular ER stores. Some other studies have shown that ROS, like H 2 O 2 can affect PLC function by pre-depleting internal Ca 2+ stores (Gerich et al, 2009;Sun et al, 2005;Volk et al, 1997). However, we found a subgroup of astrocytes that did not exhibit H 2 O 2 -induced Ca 2+ signals.…”

Section: Atp-induced Camentioning

confidence: 97%

Lipid peroxidation is essential for phospholipase C activity and IP3 related calcium signal

Domijan

Kovač²,

Abramov³

2013

Journal of Cell Science

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Reactive oxygen species (ROS) are produced in enzymatic and non-enzymatic reactions and have important roles in cell signalling but also detrimental effects. ROS-induced damage has been implicated in a number of neurological diseases; however, antioxidant therapies targeting brain diseases have been unsuccessful. Such failure might be related to inhibition of ROSinduced signalling in the brain. Using direct kinetic measures of lipid peroxidation in astrocytes and measurements of lipid peroxidation products in brain tissue, we here show that phospholipase C (PLC) preferentially cleaves oxidised lipids. Because of this, an increase in the rate of lipid peroxidation leads to increased Ca 2+ release from endoplasmic reticulum (ER) stores in response to physiological activation of purinoreceptors with ATP. Both vitamin E and its water-soluble analogue Trolox, potent ROS scavengers, were able to suppress PLC activity, therefore dampening intracellular Ca signalling. This implies that antioxidants can compromise intracellular Ca 2+ signalling through inhibition of PLC, and that PLC plays a dual role -signalling and antioxidant defence.

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Section: Atp-induced Camentioning

confidence: 97%

Lipid peroxidation is essential for phospholipase C activity and IP3 related calcium signal

Domijan

Kovač²,

Abramov³

2013

Journal of Cell Science

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“…Exposure of hippocampal neurons to subtoxic levels of hydrogen peroxide triggers the release of Ca 2? from the endoplasmic reticulum by causing the opening of both IP 3 and ryanodine receptor channels [143]. Interestingly, superoxide enhances long-term potentiation of synaptic transmission in hippocampal CA1 neurons by a mechanism requiring activation of ryanodine receptors and extracellular regulated kinases [144].…”

Section: Mitostress Versus Mithormesis and Neuroprotectionmentioning

confidence: 99%

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

et al. 2010

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The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

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“…Evidence has been found for elevated oxidative stress in individuals with DS and in Ts65Dn mice, and a number of genes important for oxidative stress are encoded on HSA21 including SOD1 and RCAN1. Not only may oxidative stress play a role in terms of inducing oxidative damage to proteins, lipids, and nucleic acids, but also reactive oxygen species have been implicated in cellular signaling pathways (Gerich et al 2009). So again, metabolism may be directly related to cellular signaling.…”

Section: Metabolomics and Dsmentioning

confidence: 99%

Molecular genetic analysis of Down syndrome

2009

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Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.

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H2O2-mediated modulation of cytosolic signaling and organelle function in rat hippocampus

Cited by 57 publications

References 61 publications

Lipid peroxidation is essential for phospholipase C activity and IP3 related calcium signal

Lipid peroxidation is essential for phospholipase C activity and IP3 related calcium signal

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

Molecular genetic analysis of Down syndrome

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