Chromatin condensation during glutamate-induced excitotoxicity of celebellar granule neurons precedes disintegration of nuclear DNA into high molecular weight DNA fragments

Bezvenyuk, Zinayida; Miettinen, Reijo; Solovyan, V. T.

doi:10.1016/s0169-328x(02)00587-9

Cited by 10 publications

(8 citation statements)

References 18 publications

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“…As shown in Figure 2A, the exposure of cells to 10 mmol/L Glu resulted in chromatin condensation but not DNA fragmentation. A similar form of chromatin condensation has recently been observed in HT22 cells and cerebellar granule neurons exposed to Glu [24,25] . Pretreatment with AA alleviated Glu-induced nuclear morphological alterations.…”

Section: Discussionsupporting

confidence: 79%

Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells

et al. 2012

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Aim: To investigate whether asiatic acid (AA), a pentacyclic triterpene in Centella asiatica, exerted neuroprotective effects in vitro and in vivo, and to determine the underlying mechanisms. Methods: human neuroblastoma Sh-SY5Y cells were used for in vitro study. Cell viability was determined with the MTT assay. hoechst 33342 staining and flow cytometry were used to examine the apoptosis. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured using fluorescent dye. PGC-1α and Sirt1 levels were examined using Western blotting. Neonatal mice were given monosodium glutamate (2.5 mg/g) subcutaneously at the neck from postnatal day (PD) 7 to 13, and orally administered with AA on PD 14 daily for 30 d. The learning and memory of the mice were evaluated with the Morris water maze test. hE staining was used to analyze the pyramidal layer structure in the CA1 and CA3 regions. Results: Pretreatment of Sh-SY5Y cells with AA (0.1-100 nmol/L) attenuated toxicity induced by 10 mmol/L glutamate in a concentration-dependent manner. AA 10 nmol/L significantly decreased apoptotic cell death and reduced reactive oxygen species (ROS), stabilized the mitochondrial membrane potential (MMP), and promoted the expression of PGC-1α and Sirt1. In the mice models, oral administration of AA (100 mg/kg) significantly attenuated cognitive deficits in the Morris water maze test, and restored lipid peroxidation and glutathione and the activity of SOD in the hippocampus and cortex to the control levels. AA (50 and 100 mg/kg) also attenuated neuronal damage of the pyramidal layer in the CA1 and CA3 regions. Conclusion: AA attenuates glutamate-induced cognitive deficits of mice and protects SH-SY5Y cells against glutamate-induced apoptosis in vitro.

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Section: Discussionsupporting

confidence: 79%

Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells

et al. 2012

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“…Our data indicate that excitotoxicity induced by KA in CGCs was not accompanied by a dramatic increase in the activity of caspase-3, -6, or -9 compared with other neurotoxicants. These results are in agreement with other studies that demonstrate that an excitotoxic treatment induces a programmed cell death process independent of caspase activation and is insensitive to caspase inhibitors (Verdaguer et al, 2002a,b;Bezvenyuk et al, 2003) Several in vitro studies have demonstrated the programmed mechanism activation role of E2F1, which has been characterized as a transcription factor that induces programmed cell death after its activation, such as p53 and c-JUN (Phillips and Vousden, 2001). Additional support for the role of E2F-1 in neuronal cell death is that CGN cultures from E2F-1-deficient mice are resistant to death when challenged with potassium deprivation, a well known neuronal death model (O'Hare et al, 2002).…”

Section: Discussionsupporting

confidence: 94%

Inhibition of Cell Cycle Pathway by Flavopiridol Promotes Survival of Cerebellar Granule Cells after an Excitotoxic Treatment

Verdaguer

Jiménez

Canudas³

et al. 2003

J Pharmacol Exp Ther

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Kainic acid (KA)-induced neuronal damage and the protective effects of flavopiridol were studied in primary cultures of rat cerebellar granule cells (CGNs). When neurons were treated with 500 M KA, the percentage of cells with condensed nuclei measured by nuclear counting increased by up to 55%. After flavopiridol treatment, an antitumoral drug that is a broad inhibitor of cyclin-dependent kinases, the percentage of condensed nuclei decreased by up to 26%. Furthermore, this KA-mediated cell death was only partially dependent on the activation of the initiator caspase-9 and the effector caspases-3 and -6. This argues for a minor role of caspases in the intracellular pathway leading to KA-induced programmed cell death in CGNs. We examined the possible implication of cell cycle proteins in KA-induced neurotoxicity. We found an increase in the expression of proliferating cell nuclear antigen and E2F-1, two proteins implicated in S-phase, by Western blot. KA increased bromodeoxyuridine incorporation in CGNs, a marker of cell proliferation, and flavopiridol attenuated this effect. These results indicated that flavopiridol decreased the expression of cell cycle markers in CGNs after KA treatment. Flavopiridol might thus be used as a preventive agent against neurodegenerative diseases associated with cell cycle activation.

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“…Previous studies have shown that excessive glutamate can trigger apoptotic changes, such as nuclear shrinkage and chromatin condensation, in neuronal cells [34]. As shown above, tanshinone IIA was able to prevent the loss of MMP induced by glutamate in SH-SY5Y cells.…”

Section: Resultsmentioning

confidence: 53%

Tanshinone IIA Inhibits Glutamate‐Induced Oxidative Toxicity through Prevention of Mitochondrial Dysfunction and Suppression of MAPK Activation in SH‐SY5Y Human Neuroblastoma Cells

Han

Wang

et al. 2017

Oxidative Medicine and Cellular Longevity

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Glutamate excitotoxicity is associated with many neurological diseases, including cerebral ischemia and neurodegenerative diseases. Tanshinone IIA, a diterpenoid naphthoquinone from Salvia miltiorrhiza, has been shown to suppress presynaptic glutamate release, but its protective mechanism against glutamate-induced neurotoxicity is lacking. Using SH-SY5Y human neuroblastoma cells, we show here that excessive glutamate exposure decreases cell viability and proliferation and increases LDH release. Pretreatment with tanshinone IIA, however, prevents the decrease in cell viability and proliferation and the increase in LDH release induced by glutamate. Tanshinone IIA also attenuates glutamate-induced oxidative stress by reducing reactive oxygen species level and malondialdehyde and protein carbonyl contents and by enhancing activities and protein levels of superoxide dismutase and catalase. We then show that tanshinone IIA prevents glutamate-induced mitochondrial dysfunction by increasing mitochondrial membrane potential and ATP content and by reducing mitochondrial protein carbonyl content. Moreover, tanshinone IIA can inhibit glutamate-induced apoptosis through regulation of apoptosis-related protein expression and MAPK activation, including elevation of Bcl-2 protein level, decrease in Bax and cleaved caspase-3 levels, and suppression of JNK and p38 MAPK activation. Collectively, our findings demonstrate that tanshinone IIA protects SH-SY5Y cells against glutamate toxicity by reducing oxidative stress and regulating apoptosis and MAPK pathways.

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Chromatin condensation during glutamate-induced excitotoxicity of celebellar granule neurons precedes disintegration of nuclear DNA into high molecular weight DNA fragments

Cited by 10 publications

References 18 publications

Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells

Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells

Inhibition of Cell Cycle Pathway by Flavopiridol Promotes Survival of Cerebellar Granule Cells after an Excitotoxic Treatment

Tanshinone IIA Inhibits Glutamate‐Induced Oxidative Toxicity through Prevention of Mitochondrial Dysfunction and Suppression of MAPK Activation in SH‐SY5Y Human Neuroblastoma Cells

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