Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain
Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain
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DOI：
10.1016/j.ymgme.2004.02.002
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发表时间：
2004-05-01
影响因子：
3.8
通讯作者：
Eccleston, E
中科院分区：
文献类型：
--
作者：
Berry, GT;Buccafusca, R;Eccleston, E
“肌醇耗竭假说”被广泛认为是锂对大脑功能的影响的解释，关于其在情绪障碍中的使用，以及对不同生物体发育和胚胎畸形诱导的损害。该假说的实质是，细胞肌醇（Ins）的缺乏，继发于锂抑制肌醇单磷酸酶和/或多肌醇多磷酸磷酸酶活性，并将Ins捕获为肌醇磷酸，导致磷脂酰肌醇（PtdIns）的抑制和肌醇信号传导的继发性损害。然而，相对低的微摩尔水平的铟，以减少哺乳动物PtdIns合成酶活性在体内的能力从来没有得到充分的测试。我们已经产生了一个致命的小鼠脑Ins缺陷模型和测量PtdIns的含量使用一种新的MALDI-TOF MS方法。我们的研究结果表明，在哺乳动物中记录的最严重的Ins缺乏症中，大脑PtdIns水平不会降低。我们的结论是，PtdIns缺乏症由于“肌醇耗竭”是不是一种机制的锂行动在大脑中，并在哺乳动物大脑中的Ins发挥另一个身份不明的作用。(C)2004年爱思唯尔公司All rights reserved.
The "inositol depletion hypothesis" has been widely held to be the explanation for both the effect of lithium on brain function, apropos of its use in mood disorders, and on the impairment of development and induction of embryonic malformations in diverse organisms. The essence of the hypothesis is that a deficiency in cellular myo-inositol (Ins), secondary to lithium inhibition of inositol monophosphatase and/or multiple inositol polyphosphate phosphatase activities with trapping of Ins as inositol phosphates, leads to a depression of phosphatidylinositol (PtdIns) and a secondary impairment in inositide signaling. However, the ability of relatively low micromolar levels of Ins to reduce mammalian PtdIns synthetase activity in vivo has never been adequately tested. We have generated a lethal murine brain Ins deficiency model and measured PtdIns content using a novel MALDI-TOF MS method. Our results show that in the most severe Ins deficiency ever recorded in a mammal, the brain PtdIns levels do not decrease. We conclude that PtdIns deficiency due to "inositol depletion" is not a mechanism of lithium action in brain, and that Ins plays another unidentified role in the mammalian brain. (C) 2004 Elsevier Inc. All rights reserved.