Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans.
Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans.
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DOI：
10.1038/npp.2015.343
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Churchill GC
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文献类型：
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作者：
Singh N;Sharpley AL;Emir UE;Masaki C;Herzallah MM;Gluck MA;Sharp T;Harmer CJ;Vasudevan SR;Cowen PJ;Churchill GC
锂仍然是治疗双相情感障碍的金标准，但有不必要的毒性和副作用。我们以前报道，依布硒啉抑制肌醇单磷酸酶（IMPase），并通过降低肌醇在动物模型中表现出锂样作用。Ebselen已在其他疾病的临床试验中进行了测试，使我们能够首次确定血脑屏障渗透剂IMPase抑制剂对人类中枢神经系统（CNS）功能的影响。我们现在报道，在一项健康受试者的双盲、安慰剂对照试验中，急性口服依布硒啉减少了前扣带皮层中的脑肌醇，这与CNS靶点参与一致。Ebselen减少慢波睡眠，并通过增加对某些情绪的识别，减少听觉惊吓范式的潜伏期和减少奖励刺激的强化来影响情绪处理。总之，依布硒啉影响磷酸肌醇循环，并对可能与双相情感障碍治疗相关的替代标志物具有CNS效应，这可以在未来的临床试验中进行测试。
Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder, which can be tested in future clinical trials.