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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we have reported that oxidative stress induced by hydrogen peroxide exacerbates the effect of an Na+ load in isolated nerve terminals, with a consequence of an ATP depletion, [Ca2+]i and [Na+]i deregulation, and collapse of mitochondrial membrane potential. In the present study, the release of glutamate in response to a combined effect of an [Na+] load and oxidative stress was measured in isolated nerve terminals over an incubation for 15 min. Exposure to hydrogen peroxide (100 micro m) had no effect on the release of glutamate, but significantly enhanced the Ca2+-independent glutamate release induced by a small [Na+] load achieved with 10 micro m veratridine. The effect of a larger Na+ load induced by 40 micro m veratridine was not further increased by hydrogen peroxide; in contrast the external Ca2+-dependent glutamate release was completely eliminated by the oxidant under this condition. The effects of oxidative stress superimposed on a Na+ load are consistent with at least two factors: (i) a relatively modest Na+ load induced by veratridine is augmented by H2O2 giving rise to an increased Ca2+-independent release of glutamate (ii) oxidative stress in combination with a larger Na+ load causes severe ATP depletion limiting the Ca2+-dependent vesicular glutamate release. Given the concurrent presence of an Na+ load and oxidative stress in ischemia/reperfusion these results indicate that the extent of the Na+ load developing during the ischemic period could determine the release of glutamate induced by an oxidative stress during reperfusion.
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PMID:Glutamate release by an Na+ load and oxidative stress in nerve terminals: relevance to ischemia/reperfusion. 1242 57

Estrogens are neuroprotective against glutamate excitotoxicity caused by an excessive rise in intracellular calcium ([Ca(2+)](i)). In this study, we demonstrate that 17 beta-estradiol (E(2)) treatment of hippocampal neurons attenuated the excitotoxic glutamate-induced rise in bulk-free [Ca(2+)](i) despite potentiating the influx of Ca(2+) induced by glutamate. E(2)-induced attenuation of bulk-free [Ca(2+)](i) depends on mitochondrial sequestration of Ca(2+), which is blocked in the presence of the combination of rotenone and oligomycin or in the presence of antimycin, which collapse the mitochondrial membrane potential, thereby preventing mitochondrial Ca(2+) transport. Release of mitochondrial Ca(2+) by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) after excitotoxic glutamate treatment resulted in a greater [Ca(2+)](i) in E(2)-treated cells, indicating an E(2)-induced increase in the mitochondrial calcium ([Ca(2+)](m)) load. The increased [Ca(2+)](m) load was accompanied by increased expression of Bcl-2, which can promote mitochondrial Ca(2+) load tolerance. These findings provide a mechanism of E(2)-induced neuronal survival by attenuation of excitotoxic glutamate [Ca(2+)](i) rise via increased mitochondrial sequestration of cytosolic Ca(2+) coupled with an increase in Bcl-2 expression to sustain mitochondrial Ca(2+) load tolerance and function.
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PMID:Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. 1260 81

Recent studies in desmin (-/-) mice have shown that the targeted ablation of desmin leads to pathological changes of the extrasarcomeric intermediate filament cytoskeleton, as well as structural and functional abnormalities of mitochondria in striated muscle. Here, we report on a novel heterozygous single adenine insertion mutation (c.5141_5143insA) in a 40-year-old patient with a distal myopathy. The insertion mutation leads to a frameshift and a truncated desmin (K239fs242). Using transfection studies in SW13 and BHK21 cells, we show that the K239fsX242 desmin mutant is incapable of forming a desmin intermediate filament network. Furthermore, it induces the collapse of a pre-existing desmin cytoskeleton, alters the subcellular distribution of mitochondria and leads to abnormal cytoplasmic protein aggregates reminiscent of desmin-immunoreactive granulofilamentous material seen in the ultrastructural analysis of the patient's muscle. Analysis of mitochondrial function in isolated saponin-permeablized skeletal muscle fibres from our patient showed decreased maximal rates of respiration with the NAD-dependent substrate combination glutamate and malate, as well as a higher amytal sensitivity of respiration, indicating an in vivo inhibition of complex I activity. Our findings suggest that the heterozygous K239fsX242 desmin insertion mutation has a dominant negative effect on the polymerization process of desmin intermediate filaments and affects not only the subcellular distribution, but also biochemical properties of mitochondria in diseased human skeletal muscle. As a consequence, the intermediate filament pathology-induced mitochondrial dysfunction may contribute to the degeneration/regeneration process leading to progressive muscle dysfunction in human desminopathies.
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PMID:On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria. 1262 Sep 71

The hypothesis that a destabilization of mitochondrial function during neuronal exposure to excitatory amino acids may be involved in the mechanism of neuronal death was examined. The mitochondrial membrane potential (Delta(psi)m) and the cytoplasmic Ca2+ concentration ([Ca2+]c) were monitored simultaneously in single cultured rat cerebellar granule cells (CGCs) loaded with tetramethylrhodamine methyl ester (TMR) and fura-2; CGCs were depolarized with K+, or exposed to excitotoxic doses of glutamate or kainate, and viability of the same neurons was studied for 24-30 h. This approach made it possible to single out the neurons that died, and to describe the changes in Delta(psi)m and [Ca2+]c that were characteristic for these neurons. Exposure to glutamate caused an increase in [Ca2+]c that was associated with a decrease in the mitochondrial TMR fluorescence, which indicates a decrease in Delta(psi)m. The neurons that failed to restore Delta(psi)m following glutamate withdrawal, also failed to restore low [Ca2+]c, and later died. Although a similar number of neurons died following kainate exposure as did after glutamate exposure, the kainate-elicited neuronal death resulted not from the collapse of Delta(psi)m but from an excessive neuronal swelling, which led to rupture of the plasma membrane. Depolarization with K+ was not neurotoxic and caused only a minor decrease in TMR fluorescence. These results indicate that in vitro glutamate and kainate destroy neurons by different mechanisms: glutamate by a failure to restore Delta(psi)m following the exposure, and kainate by an osmotic lesion of the plasma membrane.
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PMID:The difference between mechanisms of kainate and glutamate excitotoxicity in vitro: osmotic lesion versus mitochondrial depolarization. 1267

We have investigated the protective role of taurine in glutamate-mediated cell death and the involvement of mitochondria in this process. In cultured cerebellar granule cells, glutamate induces a rapid and sustained elevation in cytoplasmic free calcium ([Ca2+]i), causing the collapse of the mitochondrial electrochemical gradient (MtECG) and subsequent cell death. We found that pre-treatment with taurine, did not affect the level of calcium uptake with glutamate but rather reduced its duration; the calcium increase was transient and returned to basal levels about 10 min after adding glutamate. Furthermore, taurine reduced mitochondrial calcium concentration under non-depolarizing conditions. Treatment of cerebellar granule cells with taurine enhanced mitochondrial activity as measured by rhodamine uptake, both in the presence or absence of glutamate. We conclude that taurine prevents or reduces glutamate excitotoxicity through both the enhancement of mitochondrial function and the regulation of intracellular (cytoplasmic and mitochondrial) calcium homeostasis.
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PMID:Taurine regulates mitochondrial calcium homeostasis. 1290 39

This study describes nanofabrication of helical peptide-shelled dendrimers using a Langmuir monolayer technique. Poly(amido amine) dendrimers (G3) modified with poly(gamma-benzyl-L-glutamate) [number averaged degree of polymerization, n = 12, 17, and 34 (G3-PBLGs hereafter)] were newly prepared by graft polymerization of gamma-benzyl-L-glutamate-N-carboxy anhydride initiated with amino groups of the dendrimer surface. The hydrodynamic diameters of G3-PBLGs were determined to be 6.9 +/- 0.7, 8.2 +/- 1.0, and 11.9 +/- 1.7 nm for n = 12, 17, and 34, respectively, by means of dynamic light scattering. These values were consistent with the theoretical diameters of G3-PBLGs, which were calculated by considering the alpha-helical PBLG segment length. G3-PBLGs were found to form stable monomolecular films with high collapse pressures above 40 mN m-1 at the air-water interface. In addition, these monolayers could be successfully transferred onto various solid substrates. Circular dichroism and Fourier transfer infrared spectroscopies of the deposited G3-PBLGs monolayers showed that PBLG segments took an alpha-helical conformation over a wide range of surface pressure even on solid substrates as well as in bulk solutions. Monolayer thicknesses of these Langmuir-Blodgett films, estimated by x-ray photoelectron spectroscopy and atomic force microscopy, were compatible with the hydrodynamic diameters of G3-PBLGs.
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PMID:Nanofabrication of helical peptide-shelled dendrimers. 1291 68

Several human neurodegenerative diseases are associated with abnormal accumulations of aggregated tau proteins and glial degeneration in astrocytes, but the mechanism whereby tau proteins cause astrocytic degeneration is unclear. Here, we analyzed the biological consequences of overexpressing the longest human tau isoform in primary cultures of rat astrocytes using adenoviral-mediated gene transfer. Significantly, we found specific decreases in stable detyrosinated [glutamate (Glu)] microtubules (MTs) with concomitant increases in tubulin biosynthesis and the accumulation of acetylated, tyrosinated, alpha- and beta-tubulin. The consequences of this selective reduction in stable Glu-MTs included contemporaneous decreases in kinesin levels, collapse of the intermediate filament network, progressive disruption of kinesin-dependent trafficking of organelles, fragmentation of the Golgi apparatus that culminated in atrophy, and non-apoptotic death of astrocytes. These results suggest that reduced stable Glu-MTs is a primary consequence of tau accumulation that initiates mechanisms underlying astrocyte dysfunction and death in human neurodegenerative glial tauopathies.
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PMID:Reduction of detyrosinated microtubules and Golgi fragmentation are linked to tau-induced degeneration in astrocytes. 1462 51

Beta-amyloid (betaA) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of betaA-induced neuronal death. betaA causes a loss of mitochondrial potential in astrocytes but not in neurons. The mitochondrial response consists of Ca2+-dependent transient depolarizations superimposed on a slow collapse of potential. The slow response is both prevented by antioxidants and, remarkably, reversed by provision of glutamate and other mitochondrial substrates to complexes I and II. These findings suggest that the depolarization reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. Inhibition of NADPH oxidase by diphenylene iodonium or 4-hydroxy-3-methoxy-acetophenone blocks betaA-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents betaA-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of betaA-induced neurodegeneration.
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PMID:Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. 1472 57

Mitochondria play a central role in cell life and cell death. An increasing number of studies place mitochondrial dysfunction at the heart of disease, most notably in the heart and the central nervous system. In this article, I review some of the key features of mitochondrial biology and focus on the pathways of mitochondrial calcium accumulation. Substantial evidence now suggests that the accumulation of calcium into mitochondria may play a key role as a trigger to mitochondrial pathology, especially when that calcium uptake is accompanied by another stressor, in particular nitrosative or oxidative stress. The major process involved is the opening of the mitochondrial permeability transition pore, a large conductance pore that causes a collapse of the mitochondrial membrane potential, leading to ATP depletion and necrotic cell death or to cytochrome c release and apoptosis, depending on the rate of ATP consumption. I discuss two models in particular in which these processes have been characterized. The first is a model of oxidative stress in cardiomyocytes, in which reperfusion after ischemia causes mitochondrial calcium overload, and oxidative stress. Recent experiments suggest that cardioprotection by hypoxic preconditioning or exposure to the ATP-dependent K(+) channel opener diazoxide increases mitochondrial resistance to oxidative injury. In a second model, of calcium overload in neurons, the neurotoxicity of glutamate depends on mitochondrial calcium uptake, but the toxicity to mitochondria also requires the generation of nitric oxide. Glutamate toxicity after activation of N-methyl-D-aspartate (NMDA) receptors results from the colocalization of NMDA receptors with neuronal nitric oxide synthase (nNOS). The calcium increase mediated by NMDA receptor activation is thus associated with nitric oxide generation, and the combination leads to the collapse of mitochondrial membrane potential followed by cell death.
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PMID:Roles of mitochondria in health and disease. 1474 73

Axon guidance requires signal transduction of extracellular cues through the plasma membrane for directional motility. Here we present evidence that cholesterol- and sphingolipid-enriched membrane microdomains (lipid rafts) mediate specific guidance responses of nerve growth cones. Disruption of lipid rafts by various approaches targeting cholesterol or gangliosides selectively abolished growth cone attraction and repulsion in BDNF and netrin-1 gradients, respectively, without affecting glutamate-induced attraction. Interestingly, local raft disruption on one side of the growth cone in bath BDNF or netrin-1 produced opposite turning responses to that induced by the gradients. Raft manipulation also blocked Semaphorin 3A-induced growth cone repulsion, inhibition, and collapse. Finally, guidance responses appeared to involve raft-dependent activation of p42/p44 MAPK and ligand-induced receptor recruitment to lipid rafts. Together with the observation of asymmetric receptor-raft associations at the growth cone in guidance gradients, our findings indicate that localized signaling through membrane rafts plays a role in mediating guidance actions of extracellular cues on developing axons.
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PMID:Lipid rafts mediate chemotropic guidance of nerve growth cones. 1506 59


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