The effect of glutamate-induced excitotoxicity on DNA methylation in astrocytes in a new in vitro neuron-astrocyte-endothelium co-culture system

Zhao, Hui; Sun, Peng; Fan, Tieping; Yang, Xin; Zheng, Tiezheng; Sun, Changkai

doi:10.1016/j.bbrc.2018.12.058

Cited by 13 publications

(12 citation statements)

References 29 publications

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“…Sperm DNA methylation status may be used as an early diagnostic marker for testicular changes not detected by conventional toxicity analysis (Sakai et al 2018). Inhibition of DNA methylation in astrocytes may be a new therapeutic strategy for treating glutamate-induced excitotoxicity (Zhao et al 2019). DNA methylation levels might affect the ability of sperm to cause pregnancy during assisted reproduction and thus might be a useful area of study (Tunc and Tremellen 2009).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation may be a testicular plateau adaptation in Tibetan pig

Zhao

Tian

Cheng

et al. 2021

Journal of Applied Animal Research

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DNA methylation plays an important role in reproduction. Tibetan pigs maintain high sperm motility, even under extreme conditions at high altitudes. However, the DNA methylation mechanisms underlying testicular plateau adaptations in Tibetan pigs remain unclear. We determined the genomic DNA methylation level in the testicular tissues of Tibetan pigs living at high altitudes (TP) and of Yorkshire pigs that migrated to high altitudes (YP) using the fluorescence method. Quantitative realtime PCR and western blots were used to measure the gene and protein expression levels, respectively, of three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and hypoxia-inducible factor 2α (HIF2α). We found that the genomic DNA methylation level and the mRNA and protein expression levels of the four genes were all significantly lower in the testicular tissues of TP than YP. In short, compared with YP, the downregulation of DNA methyltransferases in the TP testes led to lower levels of genomic DNA methylation, which would facilitate higher sperm motility. Meanwhile, HIF2α expression in the TP testes was down-regulated, which might contributes to TP testes' adaption to the plateau environment. This study provided new insights into the DNA methylation mechanisms underlying plateau adaptations in TP testicles.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation may be a testicular plateau adaptation in Tibetan pig

Zhao

Tian

Cheng

et al. 2021

Journal of Applied Animal Research

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“…Compound 2 was the most cytotoxic towards neuroblastoma cell as indicated by the percentage cell viability of 51.02 ± 0.86%. However, the incorporation of various amine moieties (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) In general, all compounds except 3, 6 and 10, showed a decrease in cell viability as the concentrations increased. The increase in cell viability with an increase in concentration, as observed for 3, 6 and 10, may be due to these molecules being able to reduce baseline apoptotic processes within the cells or show proliferative effect in the neuroblastoma cells, especially compound 6.…”

Section: Cytotoxicity Studiesmentioning

confidence: 94%

“…Compound 2 was the most cytotoxic towards neuroblastoma cell as indicated by the percentage cell viability of 51.02 ± 0.86%. However, the incorporation of various amine moieties (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) led to a significant (p < 0.05) increase in percentage cell viability compared to 2. In comparison to compound 8 (69.77 ± 6.21%), the replacement of the phenylhydrazine moiety with a benzylamine moiety (3) resulted in a slight restoration of cells as showed by cell viability of 86.98 ± 6.33%.…”

Section: Cytotoxicity Studiesmentioning

confidence: 94%

“…In order to fulfil these functions, there is a need to constantly maintain low concentrations of extracellular glutamate in both neuronal and astroglial cells [ 1 , 2 ]. Under certain pathological conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), there is an increase in the level of extracellular glutamate, which becomes toxic to the neuronal cells leading to excitotoxicity [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

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4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential

et al. 2020

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The impact of excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptor overactivation and voltage gated calcium channel (VGCC) depolarization is prominent among the postulated processes involved in the development of neurodegenerative disorders. NGP1-01, a polycyclic amine, has been shown to be neuroprotective through modulation of the NMDA receptor and VGCC, and attenuation of MPP+-induced neurotoxicity. Recently, we reported on the calcium modulating effects of tricycloundecene derivatives, structurally similar to NGP1-01, on the NMDA receptor and VGCC of synaptoneurosomes. In the present study, we investigated novel 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives for their cytotoxicity, neuroprotective effects via attenuation of MPP+-induced neurotoxicity and calcium influx inhibition abilities through the NMDA receptor and VGCC using neuroblastoma SH-SY5Y cells. All compounds, in general, showed low or no toxicity against neuroblastoma cells at 10–50 µM concentrations. At 10 µM, all compounds significantly attenuated MPP+-induced neurotoxicity as evident by the enhancement in cell viability between 23.05 ± 3.45% to 53.56 ± 9.29%. In comparison to known active compounds, the derivatives demonstrated mono or dual calcium modulating effect on the NMDA receptor and/or VGCC. Molecular docking studies using the NMDA receptor protein structure indicated that the compounds are able to bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDA ion channel. The biological characteristics, together with results from in silico studies, suggest that these compounds could act as neuroprotective agents for the purpose of halting or slowing down the degenerative processes in neuronal cells.

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“…Glutamate is the major excitatory neurotransmitter of the brain and this transmitter is involved in numerous neurodegenerative diseases such as stroke, epilepsy, and CNS traumatic injury ( Zhao et al, 2019 ). Throughout these pathological events, excessive amounts of glutamate results in over-stimulating the receptors of this neurotransmitter and causes glutamate excitotoxicity which leads to increased Ca 2+ influx and finally neuronal death ( Olloquequi et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Negative Feedback Role of Astrocytes in Shaping Excitation in Brain Cell Co-cultures

Khezerlou

Prajapati

DeCoster

2021

Front. Cell. Neurosci.

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Glial cells play an important role in maintaining neuronal homeostasis and may thus influence excitability in epileptogenesis. These cells in the brain have glutamate (Glu) transporters, which remove this neurotransmitter from the extracellular space. Lack of negative (−) feedback makes local neuronal circuits more excitable and potentially contributing to epileptogenic phenomena. In this study, the role of glial cells in providing (−) feedback is shown through different models of brain cells in culture imaged for intracellular calcium concentration [(Ca2+)i]. Moreover, here we study the individual cells by putting them in categories. Neuronal networks with high and low (−) feedback were established by using anti-mitotics to deplete glial cells. Separate stimuli with very low subthreshold concentrations of Glu (250–750 nM) were added to cultures to test if the order of stimulations matter in regard to calcium dynamics outcomes. Additionally, KCl and ATP were used to stimulate glial cells. We found that for cultures high in (−) feedback, order of the stimulus was not important in predicting cellular responses and because of the complexity of networks in low (−) feedback cultures the order of stimulus matters. As an additional method for analysis, comparison of high (−) feedback cultures, and pure astrocytes was also considered. Glial cells in pure astrocyte cultures tend to be larger in size than glial cells in high (−) feedback cultures. The potential effect of (−) feedback at the blood brain barrier (BBB) was also considered for the inflammatory responses of nitric oxide (NO) production and [Ca2+]i regulation using brain microvascular endothelial cells (BMVECs). The inflammatory and calcium signaling pathways both indicate the negative feedback role of astrocytes, poised between the BBB and structures deeper within the brain, where neuronal synapses are homeostatically maintained by glial uptake of neurotransmitters.

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The effect of glutamate-induced excitotoxicity on DNA methylation in astrocytes in a new in vitro neuron-astrocyte-endothelium co-culture system

Cited by 13 publications

References 29 publications

DNA Methylation may be a testicular plateau adaptation in Tibetan pig

DNA Methylation may be a testicular plateau adaptation in Tibetan pig

4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential

Negative Feedback Role of Astrocytes in Shaping Excitation in Brain Cell Co-cultures

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