Sodium butyrate, an epigenetic interventional strategy, attenuates a stress-induced alteration of MK-801's pharmacologic action
Sodium butyrate, an epigenetic interventional strategy, attenuates a stress-induced alteration of MK-801's pharmacologic action
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DOI：
10.1016/j.euroneuro.2007.11.004
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发表时间：
2008-08-01
影响因子：
5.6
通讯作者：
Mastropaolo, John
中科院分区：
文献类型：
--
作者：
Deutsch, Stephen I.;Rosse, Richard B.;Mastropaolo, John
在小鼠暴露于冷水中的单次强迫游泳后24小时，MK-801（地佐环平）（一种非竞争性NMDA受体拮抗剂）拮抗电诱发癫痫发作的能力降低。可以想象，MK-801抗癫痫疗效的降低反映了单次应激后24小时基因表达变化引起的NMDA受体介导的神经传递的应激诱导改变。最近，影响基因表达的表观遗传干预策略已经在各种神经精神疾病的临床前模型中进行了测试，包括亨廷顿病和重度抑郁症，所述基因的调控受核小体中组蛋白的乙酰化状态控制，所述组蛋白是组蛋白和双链DNA的启动子区的八聚体复合物。这些策略在癌症生物学中得到了广泛的研究。在当前研究中，当在应激时给予丁酸钠（1.5 g/kg，ip）时，应激诱导的MK-801提高诱发强直性后肢伸展阈值电压的能力降低的严重程度降低。先前的研究表明，该剂量的丁酸钠可靠地增加了小鼠海马和大脑皮层中H3和H4组蛋白的乙酰化状态。因此，MK-801的抗癫痫疗效的应力诱导的降低的衰减可能是由于核小体核心中的组蛋白的乙酰化增加和基因表达的促进。这些数据鼓励发展表观遗传策略，以防止压力的一些有害后果。由爱思唯尔公司出版
Twenty-four hours after mice are exposed to a single session of forced swimming in cold water, the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically precipitated seizures is reduced. Conceivably, this reduction in MK-801's antiseizure efficacy reflects a stress-induced alteration in NMDA receptor-mediated neurotransmission due to changes in gene expression 24 h after a single stress. Recently, epigenetic interventional strategies impacting expression of genes whose regulation is controlled by the acetylation status of histone proteins in the nucleosome, an octomeric complex of histone proteins and promoter regions of double-stranded DNA, have been tested in preclinical models of various neuropsychiatric disorders, including Huntington disease and major depression. These strategies have been studied extensively in cancer biology. In the current investigation, the severity of the stress-induced reduction of MK-801's ability to raise the threshold voltage for the elicitation of tonic hindlimb extension was reduced when sodium butyrate (1.5 g/kg, ip) was administered around the time of stress. Prior research showed that this dose of sodium butyrate reliably increased the acetylation status of H3 and H4 histone proteins in the hippocampus and cerebral cortex of mice. Thus, the attenuation of the stress-induced reduction of MK-801's antiseizure efficacy may be due to the increased acetylation of histone proteins in the nucleosomal core and promotion of gene expression. These data encourage development of epigenetic strategies to prevent some of the deleterious consequences of stress. Published by Elsevier B.V.