Valproic Acid Phase Shifts the Rhythmic Expression of PERIOD2::LUCIFERASE
Valproic Acid Phase Shifts the Rhythmic Expression of PERIOD2::LUCIFERASE
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DOI：
10.1177/0748730411419775
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Lundkvist, Gabriella B. S.
中科院分区：
文献类型：
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作者：
Johansson, Anne-Sofie;Brask, Johan;Lundkvist, Gabriella B. S.
丙戊酸（VPA）是一种用于治疗双相情感障碍的抗惊厥药，双相情感障碍是一种与昼夜节律紊乱相关的精神疾病。关于VPA如何影响昼夜节律知之甚少。作者培养了转基因PERIOD 2：：LUCIFERASE（PER 2：：LUC）小鼠的含有昼夜节律主脑起搏器、视交叉上核（SCN）和皮肤成纤维细胞的组织，并通过测量生物发光研究了VPA对昼夜节律PER 2：：LUC节律的影响。当在对应于最低（谷值，类似于ZT 0）PER 2：：LUC表达的时间点给药时，VPA（1 mM）显著使PER 2：：LUC节律时相提前，但当在最高（峰值，类似于ZT 12）蛋白表达时给药时，VPA（1 mM）使PER 2：：LUC节律时相延迟。此外，在ZT 12或接近ZT 12的时间点，它显著增加了PER 2：：LUC振荡的总体幅度，但对周期没有影响。对小鼠和人成纤维细胞的实时PCR分析显示，VPA处理2小时后，其他时钟基因的表达增加。由于已知VPA可抑制组蛋白脱乙酰化，因此作者用已确定的组蛋白脱乙酰化抑制剂曲马斯他丁A（TSA; 20 ng/mL）处理培养物，以比较VPA和TSA对分子节律性的影响。他们发现TSA对PER 2：：LUC节律的影响与VPA相似。此外，VPA和TSA显著增加组蛋白H3的乙酰化，但相比之下，对组蛋白H4的乙酰化作用较小。锂是另一种常用的治疗双相情感障碍。因此，作者还研究了氯化锂（LiCl; 10 mM）对PER 2：：LUC节律的影响。LiCl延迟相，但与VPA和TSA相反，LiCl延长PER 2：：LUC期，对组蛋白乙酰化没有影响。这些结果表明，VPA可延迟或提前PERIOD 2：：LUCIFERASE节律的相位，并增加振幅，这取决于应用的昼夜节律时间。此外，作者表明，LiCl延迟了PER 2：：LUC节律的相位并延长了其周期，证实了先前关于昼夜锂效应的报道。这些不同的分子效应可能是VPA和锂的不同计时效应的基础。
Valproic acid (VPA) is an anticonvulsant used to treat bipolar disorder, a psychiatric disease associated with disturbances in circadian rhythmicity. Little is known about how VPA affects circadian rhythms. The authors cultured tissues containing the master brain pacemaker for circadian rhythmicity, the suprachiasmatic nuclei (SCN), and skin fibroblasts from transgenic PERIOD2::LUCIFERASE (PER2::LUC) mice and studied the effect of VPA on the circadian PER2::LUC rhythm by measuring bioluminescence. VPA (1 mM) significantly phase advanced the PER2::LUC rhythm when applied at a time point corresponding to the lowest (trough, similar to ZT 0) PER2::LUC expression but phase delayed the PER2::LUC rhythm when the drug was administered at the time of highest (peak, similar to ZT 12) protein expression. In addition, it significantly increased the overall amplitude of PER2::LUC oscillations at time points at or close to ZT 12 but had no effect on period. Real-time PCR analyses on mouse and human fibroblasts revealed that expressions of other clock genes were increased after 2 h treatment with VPA. Because VPA is known to inhibit histone deacetylation, the authors treated cultures with an established histone deacetylation inhibitor, trichostatin A (TSA; 20 ng/mL), to compare the effect of VPA and TSA on molecular rhythmicity. They found that TSA had similar effects on the PER2::LUC rhythm as VPA. Furthermore, VPA and TSA significantly increased acetylation on histone H3 but in comparison little on histone H4. Lithium is another commonly used treatment for bipolar disorder. Therefore, the authors also studied the impact of lithium chloride (LiCl; 10 mM) on the PER2::LUC rhythm. LiCl delayed the phase, but in contrast to VPA and TSA, LiCl lengthened the PER2::LUC period and had no effect on histone acetylation. These results demonstrate that VPA can delay or advance the phase, as well as increase the amplitude, of the PERIOD2::LUCIFERASE rhythm depending on the circadian time of application. Furthermore, the authors show that LiCl delays the phase and lengthens the period of the PER2::LUC rhythm, confirming previous reports on circadian lithium effects. These different molecular effects may underlie differential chronotherapeutic effects of VPA and lithium.