Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions.
Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions.
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DOI：
10.1007/s11306-010-0208-9
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发表时间：
2010-06-01
期刊：
影响因子：
3.6
通讯作者：
Kaddurah-Daouk, Rima
中科院分区：
文献类型：
--
作者：
Fan, Teresa W-M;Yuan, Peixiong;Lane, Andrew N.;Higashi, Richard M.;Wang, Yun;Hamidi, Anahita B.;Zhou, Rulun;Guitart, Xavier;Chen, Guang;Manji, Husseini K.;Kaddurah-Daouk, Rima
关键词：
尽管锂在治疗双相情感障碍（BPD）方面的疗效已经确立，但其作用的分子机制仍然难以捉摸。新开发的稳定同位素分辨代谢组学（SIRM）是一种强大的方法，可用于系统地阐明锂如何影响神经胶质和神经元代谢途径和活动，最终导致破译其分子作用机制。采用核磁共振（NMR）和气相色谱-质谱（GC-MS）分析了锂对培养的大鼠星形胶质细胞和神经元中三种不同的13 C-标记前体（[U-13 C]-葡萄糖、13 C-3-乳酸和13 C-2，3-丙氨酸）代谢的影响。使用[U-13 C]-葡萄糖，锂被证明可以增强星形胶质细胞和神经元中的糖酵解活性和部分克雷布斯循环活性，特别是回补丙酮酸羧化（PC）。PC通路以前被认为在星形胶质细胞中是活跃的，但在神经元中不存在。锂还刺激细胞外释放13 C标记的-乳酸，-丙氨酸（Ala），-柠檬酸，和-谷氨酰胺（Gln）的星形胶质细胞。使用13 C-3-乳酸或13 C-2，3-Ala作为示踪剂的神经元通路的询问表明神经元在克雷布斯循环中利用乳酸和Ala的高能力，特别是在通过PC和正常循环活性产生标记的Asp和Glu中。长时间的锂处理增强乳酸代谢通过PC，但抑制乳酸氧化通过正常的克雷布斯循环神经元。星形胶质细胞和神经元中糖酵解、PC和克雷布斯循环活性的这种锂调节以及星形胶质细胞释放燃料底物应有助于补充用于Glu合成的克雷布斯循环底物，同时满足神经元对能量的需求。对这些代谢特征的分子调控的进一步研究应该为心境障碍的病理生理学和早期诊断标志物以及有效治疗的新靶点提供新的见解。
Despite the long-established therapeutic efficacy of lithium in the treatment of bipolar disorder (BPD), its molecular mechanism of action remains elusive. Newly developed stable isotope-resolved metabolomics (SIRM) is a powerful approach that can be used to elucidate systematically how lithium impacts glial and neuronal metabolic pathways and activities, leading ultimately to deciphering its molecular mechanism of action. The effect of lithium on the metabolism of three different 13C-labeled precursors ([U-13C]-glucose, 13C-3-lactate or 13C-2,3-alanine) was analyzed in cultured rat astrocytes and neurons by nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GC-MS). Using [U-13C]-glucose, lithium was shown to enhance glycolytic activity and part of the Krebs cycle activity in both astrocytes and neurons, particularly the anaplerotic pyruvate carboxylation (PC). The PC pathway was previously thought to be active in astrocytes but absent in neurons. Lithium also stimulated the extracellular release of 13C labeled-lactate, -alanine (Ala), -citrate, and -glutamine (Gln) by astrocytes. Interrogation of neuronal pathways using 13C-3-lactate or 13C-2,3-Ala as tracers indicated a high capacity of neurons to utilize lactate and Ala in the Krebs cycle, particularly in the production of labeled Asp and Glu via PC and normal cycle activity. Prolonged lithium treatment enhanced lactate metabolism via PC but inhibited lactate oxidation via the normal Krebs cycle in neurons. Such lithium modulation of glycolytic, PC and Krebs cycle activity in astrocytes and neurons as well as release of fuel substrates by astrocytes should help replenish Krebs cycle substrates for Glu synthesis while meeting neuronal demands for energy. Further investigations into the molecular regulation of these metabolic traits should provide new insights into the pathophysiology of mood disorders and early diagnostic markers, as well as new target(s) for effective therapies.
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影响因子：
2.7
作者：
Hedgepeth, CM;Conrad, LJ;Klein, PS
通讯作者：
Klein, PS
DOI：
10.1073/pnas.93.7.2719
发表时间：
1996-04-02
影响因子：
11.1
作者：
Hoshi, M;Takashima, A;Imahori, K
通讯作者：
Imahori, K
影响因子：
11
作者：
Engel, S. R.;Creson, T. K.;Chen, G.
通讯作者：
Chen, G.
影响因子：
3.3
作者：
BERGGREN, U
通讯作者：
BERGGREN, U
影响因子：
37.3
作者：
Fan TW;Lane AN;Higashi RM;Farag MA;Gao H;Bousamra M;Miller DM
通讯作者：
Miller DM