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首页> 外文期刊>BMC Neuroscience >Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death
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Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death

机译：马雌激素通过调节参与编程的细胞死亡的调节蛋白，差异抑制神经元细胞中的谷氨酸诱导的DNA片段化

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Background Recent data indicate that excitotoxicity of high levels of neurotransmitter glutamate may be mediated via programmed cell death (apoptosis) and that it can be prevented in HT22 mouse hippocampal cells by various equine estrogens with Δ8,17β-estradiol (Δ8,17β-E2) being the most potent. In order to delineate the mechanism(s), glutamate-induced cell death of HT22 cells was assessed by measuring (a) DNA fragmentation in the presence or absence of 11 equine estrogens (components of the drug CEE); (b) cell death and (c) levels of anti-apoptotic (Bcl-2) and proapoptotic (Bax) proteins in the presence or absence of two equine estrogens, Δ8,17β-E2 and 17β-estradiol (17β-E2) by LDH release assay and Western blot analysis respectively. Results Glutamate treatment induced cell death was time and dose-dependent. After 18 to 24 h, glutamate induced DNA fragmentation and morphological characteristics of apoptotic cell death. DNA fragmentation and morphological changes induced by 10 mM glutamate were completely inhibited by some equine estrogens. Exposure of cells to various concentrations of glutamate, resulted in a significant increase in cell death associated LDH release that was time-dependent. Both Δ8,17β-E2 and 17β-E2 inhibited the glutamate-induced LDH release and cell death in a dose-dependent manner with Δ8,17β-E2 being 10 times more potent than 17β-E2. Western blot analysis indicated that glutamate also significantly decreased the levels of Bcl-2 and increased Bax levels. This glutamate-induced change in the ratio of Bcl-2 to Bax was reversed by estrogens with Δ8,17β-E2 being more potent. Conclusions In HT22 mouse hippocampal cells, glutamate induced apoptosis that was associated with DNA fragmentation, morphological changes and up-regulation of the pro-apoptotic protein Bax and down-regulation of the anti-apoptotic protein Bcl-2. This apoptotic process was differentially prevented by some equine estrogens with Δ8,17β-E2 being more potent than 17β-E2. Since HT22 cells lacked both glutamate and estrogen receptors, the neuroprotective effects of estrogens most likely involve both genomic and non-genomic mechanisms. Since Δ8-estrogens are less feminizing estrogens than 17β-E2, further chemical modifications of these Δ8-estrogens may provide more selective estrogens that will be useful in the prevention of neurodegenerative diseases such as Alzheimer's and Parkinson's in both aging men and women.
机译：背景技术近期数据表明，高水平的神经递质谷氨酸抑制毒素可以通过编程的细胞死亡（细胞凋亡）介导，并且可以通过各种标准雌激素在HT22小鼠海马细胞中通过δ 8 ，17β - 雌二醇（δ 8 ，17β-e 2 是最有效的。为了描绘机制，通过在存在或不存在11只马雌激素（药物CEE的组分）中测量（a）DNA碎片来评估HT22细胞的谷氨酸诱导的HT22细胞的细胞死亡; （b）细胞死亡和（c）抗凋亡（Bcl-2）和促凋亡（Bax）蛋白在存在或不存在两种马雌激素中，δ 8 ，17β-e 2 和17β-雌二醇（17β-e 2 ）。结果谷氨酸处理诱导的细胞死亡是时间和剂量依赖性。 18至24小时后，谷氨酸诱导的DNA碎片和凋亡细胞死亡的形态特征。由一些马雌激素完全抑制10mM谷氨酸诱导的DNA片段化和形态学变化。细胞暴露于各种浓度的谷氨酸浓度，导致细胞死亡相关LDH释放的显着增加，该抑制性是时间依赖性的。 δ 8 ，17β-e 2 和17β-e 2 ，17β-e 2 比17β-e 2 更高的10倍。 Western印迹分析表明，谷氨酸也显着降低了Bcl-2的水平和增加的Bax水平。这种谷氨酸诱导的Bcl-2与Bax比的变化通过δ 8 ，17β-E 2 更有效的雌激素反转。结论HT22小鼠海马细胞，谷氨酸诱导的凋亡与DNA碎裂，形态变化和抗凋亡蛋白Bcl-2的下调和下调的形态变化和上调相关的细胞凋亡。这种凋亡过程由δ 8 ，17β-e 2 比17β-e 2 更有效地防止了δ 8℃。由于HT22细胞缺乏谷氨酸和雌激素受体，因此雌激素的神经保护作用最有可能涉及基因组和非基因组机制。由于δ 8 - 雌激素比17β-e 2 ，因此这些δ 8 -eStrogens的进一步的化学修饰可以提供更多选择性雌激素这将是在预防神经变性疾病（如Alzheimer和Parkinson）的衰老中有用。

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