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首页> 外文期刊>The European Journal of Neuroscience >Anti-apoptotic effects of allopregnanolone on P19 neurons.
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Anti-apoptotic effects of allopregnanolone on P19 neurons.

机译：阿洛帕那洛酮对P19神经元的抗凋亡作用。

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摘要

Progesterone and its metabolites are potent allosteric modulators of GABA(A) receptor function, through a direct, non-genomic interaction with specific receptor subtypes. In addition, fluctuations in the concentration of progesterone, and allopregnanolone in particular, have been shown to modulate GABA(A) receptor gene expression and activity. In this study, mouse P19 cells were induced to differentiate into post-mitotic neurons which express specific neuronal markers, including GABA(A) and N-methyl-d-aspartate (NMDA) receptors. Apoptotic cell death, induced in the presence of NMDA, was efficiently prevented by allopregnanolone and dehydroepiandrosterone (DHEA) but not DHEA sulfate. Apoptosis was accompanied by cytochrome c release to the cytoplasm and Bax translocation to the mitochondria, while the levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL remained unchanged. In the presence of the most potent neurosteroid, allopregnanolone, DNA fragmentation as well as cytochrome c and Bax translocationwere prevented. On the other hand, short-term exposure (1-20 microm, 24 h) of P19-derived neurons to allopregnanolone and DHEA significantly increased the levels of alpha1 and beta2 mRNAs of GABA(A) receptor, while the levels of NR1 mRNA of NMDA receptor were not altered. These results suggest that neurosteroids, interfering with the mitochondrial apoptotic pathway, are able to act as survival factors in neuronal cells, while they contribute to GABA(A) receptor plasticity modulating the expression of its subunits.
机译：孕酮及其代谢产物通过与特定受体亚型的直接，非基因组相互作用，是GABA（A）受体功能的有效变构调节剂。此外，已证明孕酮，尤其是去甲孕烷醇酮的浓度波动会调节GABA（A）受体基因的表达和活性。在这项研究中，小鼠P19细胞被诱导分化为有丝分裂后神经元，这些神经元表达特定的神经元标记，包括GABA（A）和N-甲基-d-天冬氨酸（NMDA）受体。异戊烷醇酮和脱氢表雄酮（DHEA）可有效预防在NMDA存在下诱导的凋亡细胞死亡，而硫酸DHEA则不能。凋亡伴随着细胞色素c释放到细胞质和Bax易位到线粒体，而抗凋亡蛋白Bcl-2和Bcl-xL的水平保持不变。在存在最有效的神经类固醇的情况下，可预防阿洛培那那龙，DNA断裂以及细胞色素c和Bax易位。另一方面，P19衍生神经元短期暴露于Allopregnanolone和DHEA（1-20 microm，24 h）会显着增加GABA（A）受体的alpha1和beta2 mRNA水平，而NR1 mRNA的水平则升高。 NMDA受体未改变。这些结果表明，神经甾体干扰线粒体的凋亡途径，能够充当神经元细胞中的生存因子，同时它们有助于GABA（A）受体可塑性调节其亚基的表达。

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